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Cited by 496Autophagy in Disease and TherapyRenal Diseases and GlomerulopathiesChronic Kidney Disease and Diabetes

Autophagy in kidney homeostasis and disease

Open access
Tang, Chengyuan, Livingston, Man J., Liu, Zhiwen, Dong, Zheng·2020·Nature Reviews Nephrology
DOI 10.1038/s41581-020-0309-2PMC PMC7868042
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Abstract

Autophagy is a conserved lysosomal pathway for the degradation of cytoplasmic components. Basal autophagy in kidney cells is essential for the maintenance of kidney homeostasis, structure and function. Under stress conditions, autophagy is altered as part of the adaptive response of kidney cells, in a process that is tightly regulated by signalling pathways that can modulate the cellular autophagic flux - mammalian target of rapamycin, AMP-activated protein kinase and sirtuins are key regulators of autophagy. Dysregulated autophagy contributes to the pathogenesis of acute kidney injury, to incomplete kidney repair after acute kidney injury and to chronic kidney disease of varied aetiologies, including diabetic kidney disease, focal segmental glomerulosclerosis and polycystic kidney disease. Autophagy also has a role in kidney ageing. However, questions remain about whether autophagy has a protective or a pathological role in kidney fibrosis, and about the precise mechanisms and signalling pathways underlying the autophagy response in different types of kidney cells and across the spectrum of kidney diseases. Further research is needed to gain insights into the regulation of autophagy in the kidneys and to enable the discovery of pathway-specific and kidney-selective therapies for kidney diseases and anti-ageing strategies.

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Crossref · 10.1038/s41581-020-0309-2

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  • Findingcitation

    Mitochondrial turnover is minimal in S3 segment proximal tubules under control conditions.

    “mitochondrial turnover was minimal in S3 segment proximal tubules under control conditions”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Livingston, M. J. et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy 15, 2142–2162 (2019). source

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  • Findingcitation

    Mitophagy is observed at much lower levels in glomeruli than in cortical proximal tubules.

    “Mitophagy was also observed at much lower levels in glomeruli compared with cortical proximal tubules”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Livingston, M. J. et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy 15, 2142–2162 (2019). source

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  • Findingcitation

    BNIP3-mediated mitophagy provides renoprotection during ischaemic acute kidney injury.

    “We subsequently demonstrated that induction of BCL-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy also provided renoprotection during ischaemic AKI”
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    • cites [89] Tang, C. et al. Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell Death Dis. 10, 677 (2019). source

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  • Findingcitation

    Kidney ischaemic preconditioning promotes clearance of damaged mitochondria via mitophagy to protect tubular cells and kidneys against ischaemic injury.

    “we demonstrated that kidney IPC promoted the clearance of damaged mitochondria via mitophagy to protect tubular cells and kidneys against ischaemic injury”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Livingston, M. J. et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy 15, 2142–2162 (2019). source

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  • Premisecitation

    Cytoskeleton components and motor proteins mediate autophagosome movement to lysosomes for tethering, followed by SNARE-mediated fusion.

    “Cytoskeleton components and cytoskeleton-related motor proteins mediate the movement of autophagosomes to lysosomes for tethering, followed by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated fusion”
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    • cites [12] Lorincz, P. & Juhasz, G. Autophagosome-lysosome fusion. J. Mol. Biol. 432, 2462–2482 (2020). source

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    Findingcitation

    Under control conditions, mice have high mitophagy in some cortical proximal tubules, with mitolysosomes predominantly near the apical membrane.

    “under control conditions mice had a high level of mitophagy in some cortical proximal tubules, where mitolysosomes were predominantly observed near the apical membrane”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Livingston, M. J. et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy 15, 2142–2162 (2019). source

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    Findingown data

    Kidney ischaemia-reperfusion injury dramatically induces mitophagy in proximal tubules, which is partially abrogated in Pink1 and/or Park2 knockout mice.

    “We reported a dramatic induction of mitophagy in proximal tubules during kidney IRI, which was partially abrogated in mice with a single or double knockout of the mitophagy genes Pink1 and Park2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Tang, C. et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 14, 880–897 (2018). source

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    Premisecitation

    Active AMPK induces autophagy by directly phosphorylating ULK1 or by phosphorylating tuberin or RAPTOR to inhibit mTORC1.

    “Active AMPK induces autophagy through direct phosphorylation of ULK1, or through the phosphorylation of tuberin or regulatory-associated protein of mTOR (RAPTOR; encoded by RPTOR) to inhibit mTORC1”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Lee, J. W., Park, S., Takahashi, Y. & Wang, H. G. The association of AMPK with ULK1 regulates autophagy. PLoS One 5, e15394 (2010). source

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    Premisecitation

    The ULK1-ULK2 complex is a major component in the initiation of autophagy.

    “The complex formed by serine/threonine protein kinases ULK1, ULK2 and other protein partners is a major component in the initiation of autophagy”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Park, J. M. et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547–564 (2016). source

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    • cites [7] Park, J. M. et al. ULK1 phosphorylates Ser30 of BECN1 in association with ATG14 to stimulate autophagy induction. Autophagy 14, 584–597 (2018). source

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    Premisecitation

    SIRT1 crosstalks with mTOR and AMPK pathways by interacting with hamartin-tuberin and deacetylating LKB1.

    “SIRT1 crosstalks with the mTOR and AMPK pathways by interacting with hamartin–tuberin and deacetylating LKB1”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Lan, F., Cacicedo, J. M., Ruderman, N. & Ido, Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283, 27628–27635 (2008). source

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    • cites [34] Hou, X. et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283, 20015–20026 (2008). source

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    Premisecitation

    Selective autophagy removes specific cargoes: mitochondria by mitophagy, lysosomes by lysophagy, protein aggregates by aggrephagy, and lipid droplets by lipophagy.

    “autophagy can also selectively remove specific cargoes, such as mitochondria by mitophagy, lysosomes by lysophagy, protein aggregates by aggrephagy and lipid droplets by lipophagy”
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    • cites [13] Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242 (2018). source

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    Premisecitation

    Under starvation, mTORC1 is suppressed and dissociates from the ULK1-ULK2 complex, allowing AMPK to activate ULK1 and induce autophagy.

    “Under starvation, mTORC1 is suppressed and dissociates from the ULK1–ULK2 complex, allowing ULK1 to be activated by AMPK to induce autophagy”
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    • cites [17] Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981–1991 (2009). source

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    Basal autophagy removes dysfunctional organelles and long-lived proteins to maintain cellular homeostasis.

    “Basal autophagy removes potentially dysfunctional organelles and long-lived proteins to maintain cellular homeostasis”
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    Premisecitation

    Intracellular stress from reactive oxygen species, endoplasmic reticulum stress, hypoxia, DNA damage, and immune signalling can stimulate autophagy.

    “Intracellular stress, which can be induced by reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, hypoxia, DNA damage and immune signalling, has also been demonstrated as a potential stimulator of autophagy”
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    • cites [14] Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010). source

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    Premisecitation

    Two ubiquitin-like conjugation systems, ATG12-ATG5-ATG16L and LC3, control autophagosome expansion and completion.

    “Two ubiquitin (Ub)-like conjugation systems, the ATG12–ATG5–ATG16L system and the microtubule-associated protein 1 light chain 3 (MAP1LC3; also known as LC3) system control the expansion and completion of the autophagosome”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Walczak, M. & Martens, S. Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation. Autophagy 9, 424–425 (2013). source

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    Premisecitation

    mTORC1 is a master regulator of autophagy activated by amino acids or growth factors such as insulin and insulin-like growth factor-1.

    “mTORC1 is a master regulator of autophagy that is activated by amino acids or growth factors, such as insulin and insulin-like growth factor-1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020). source

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    Premisenone given

    Autophagy has a role in kidney ageing.

    “Autophagy also has a role in kidney ageing.”
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    Premisenone given

    Autolysosomes disintegrate after autophagy terminates, and autophagic lysosome reformation recycles lysosomal membrane proteins and regenerates lysosomes.

    “autolysosomes are not permanent and disintegrate once autophagy is terminated. This process, called autophagic lysosome reformation (ALR), allows recycling of lysosomal membrane proteins and regeneration of lysosomes from autolysosomes”
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    Premisenone given

    Mitophagy is predominantly mediated by LC3-associated autophagy receptors via ubiquitin-dependent and ubiquitin-independent pathways.

    “Mitophagy is the best-described form of selective autophagy and is predominantly mediated by LC3-associated autophagy receptors via both Ub-dependent and Ub-independent pathways”
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    Premisecitation

    AMPK and mTORC1 can both be phosphorylated and inhibited by ULK1, creating crosstalk.

    “both AMPK and mTORC1 can be phosphorylated and inhibited by ULK1, which creates a complex crosstalk”
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    • cites [27] Loffler, A. S. et al. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 7, 696–706 (2011). source

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    Premisereasoning

    AMPK positively regulates autophagy.

    “AMPK positively regulates autophagy.”
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    Premisecitation

    The class III PI3K complex regulates vesicle nucleation and phagophore formation.

    “the class III phosphoinositide 3-kinase (PI3K) complex regulates vesicle nucleation and phagophore formation”
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    • cites [9] Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519–530 (2001). source

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    • cites [10] Zhong, Y. et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11, 468–476 (2009). source

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    Premisecitation

    Podocyte-specific Mtor-knockout mice accumulate autophagosomes and autolysosomes and develop severe proteinuria and kidney failure shortly after birth, suggesting mTOR-associated ALR is important for podocyte health.

    “Podocyte-specific Mtor-knockout mice accumulated autophagosomes and autolysosomes within podocytes, and developed severe proteinuria and kidney failure shortly after birth, suggesting that mTOR-associated ALR might be important for podocyte health”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Cina, D. P. et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J. Am. Soc. Nephrol. 23, 412–420 (2012). source

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    Premisecitation

    JAK2 modulates basal autophagy in podocytes by facilitating STAT1 nuclear translocation, where STAT1 binds the Tfeb promoter and induces its expression.

    “Tyrosine protein kinase JAK2 was also reported to modulate basal autophagy in podocytes by facilitating the translocation of signal transducer and activator of transcription 1 (STAT1) to the nucleus, where it binds to the Tfeb promoter to induces its expression”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Alghamdi, T. A. et al. Janus kinase 2 regulates transcription factor EB expression and autophagy completion in glomerular podocytes. J. Am. Soc. Nephrol. 28, 2641–2653 (2017). source

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    Premisecitation

    Acute induction of Atg5 deletion in 12-week-old podocyte-specific knockout mice triggers rapid albuminuria, indicating basal autophagy is crucial for podocyte function.

    “the acute induction of Atg5 deletion in 12-week-old mice triggered a rapid onset of albuminuria, indicating that basal autophagy is crucial for the maintenance of podocyte function”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010). source

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  • May combine two claims.

    Premisecitation

    Mice with glomerular endothelial cell-specific Atg5 deletion (Cdh5-Cre) show slight glomerular capillary dilation, podocyte foot process effacement, and loss of glomerular endothelial fenestrations from 10 weeks of age, without apparent functional defects up to 20 weeks.

    “researchers observed slight dilation of glomerular capillaries, podocyte foot process effacement and loss of glomerular endothelial fenestrations in the glomerular capillary loops from 10 weeks of age; however, functional defects, as assessed by urinary creatinine and blood urea nitrogen (BUN), were not apparent up to 20 weeks of age”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Lenoir, O. et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11, 1130–1145 (2015). source

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    Premisecitation

    Rapamycin treatment for 3 days inhibits mTORC1 and activates AMPK, inducing autophagy; 3 weeks inactivates AMPK and counteracts the pro-autophagic effect, returning autophagy to baseline.

    “Treatment with rapamycin for 3 days inhibited mTORC1 activity and concurrently activated AMPK in podocytes, which led to autophagy induction, whereas 3 weeks of treatment with rapamycin inactivated AMPK and counteracted the pro-autophagic effect achieved by mTORC1 inhibition and thus autophagy levels returned to the baseline observed in untreated mice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Bork, T. et al. Podocytes maintain high basal levels of autophagy independent of mtor signaling. Autophagy https://doi.org/10.1080/15548627.2019.1705007 (2019). source

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    Interpretationreasoning

    Low basal autophagy is essential for proximal tubule epithelial cell function under normal conditions, and proximal tubules rely on basal autophagy more than other tubular segments.

    “These findings suggest that low levels of basal autophagy are essential to the maintenance of PTEC function under normal conditions and that proximal tubules rely on basal autophagy more than other tubular segments.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Liu, S. et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8, 826–837 (2012). source

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    • cites [57] Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011). source

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    Premisecitation

    In mice, selective deletion of Atg5 or Atg7 in proximal tubules causes progressive kidney damage and premature kidney ageing, with damaged mitochondria, sequestosome 1 and ubiquitin-positive aggregates, tubular apoptosis, and tubulointerstitial fibrosis compared with wild-type.

    “selective deletion of Atg5 or Atg7 in proximal tubules resulted in progressive kidney damage and premature kidney ageing, as demonstrated by an accumulation of damaged mitochondria, sequestosome 1 and Ub-positive aggregates, as well as elevated tubular cell apoptosis and kidney tubulointerstitial fibrosis compared with wild-type controls”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Liu, S. et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8, 826–837 (2012). source

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    • cites [57] Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011). source

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    Interpretationcitation

    TASCCs allow simultaneous activation of anabolic and catabolic processes, facilitating mTOR-controlled synthesis of secretory proteins with energy or building blocks from constitutive autophagy.

    “TASCCs provide cells with a mechanism for simultaneous activation of anabolic and catabolic processes, which facilitates mTOR-controlled synthesis of secretory proteins with sources of energy or building blocks provided by constitutive autophagy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011). source

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    Premisecitation

    Inducible podocyte-specific deletion of mTOR, prorenin, or VPS34 causes severe glomerulosclerosis and proteinuria, highlighting the importance of intact autophagic flux for podocyte homeostasis.

    “mice with lysosomal dysfunction in podocytes, induced by inducible podocyte-specific deletion of the genes encoding mTOR, prorenin or PI3K catalytic subunit type 3 (also known as VPS34) developed severe glomerulosclerosis and proteinuria”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [47] Bechtel, W. et al. Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J. Am. Soc. Nephrol. 24, 727–743 (2013). source

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    • cites [48] Chen, J., Chen, M. X., Fogo, A. B., Harris, R. C. & Chen, J. K. mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J. Am. Soc. Nephrol. 24, 198–207 (2013). source

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    • cites [49] Cina, D. P. et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J. Am. Soc. Nephrol. 23, 412–420 (2012). source

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    • cites [50] Oshima, Y. et al. Prorenin receptor is essential for normal podocyte structure and function. J. Am. Soc. Nephrol. 22, 2203–2212 (2011). source

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    Premisecitation

    Podocytes have normal autophagic flux, as chloroquine caused rapid accumulation of LC3-GFP puncta.

    “blockade of autophagosomal degradation with the lysosomal inhibitor chloroquine induced a rapid accumulation of LC3–GFP puncta in podocytes, suggesting that these cells had a normal autophagic flux”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010). source

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    Premisecitation

    In glomeruli, podocyte-specific AMPK activity is increased in mTORC1 hyperactivation and suppressed in mTORC1 hypoactivation.

    “In glomeruli, podocyte-specific AMPK activity was increased in mice with mTORC1 hyperactivation and suppressed in mice with mTORC1 hypoactivation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Bork, T. et al. Podocytes maintain high basal levels of autophagy independent of mtor signaling. Autophagy https://doi.org/10.1080/15548627.2019.1705007 (2019). source

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    Premisecitation

    AICAR treatment results in similarly high podocyte autophagy in mTORC1 hyperactivation, hypoactivation, and wild-type mice compared with untreated, suggesting AMPK-induced autophagy is mTORC1-independent in podocytes.

    “Short-term (3 days) and long-term (3 weeks) treatment with AICAR resulted in similarly high levels of podocyte autophagy in mice with podocyte-specific mTORC1 hyperactivation or hypoactivation and in wild-type mice, compared with mice without AICAR treatment, suggesting that autophagy induction by AMPK is mTORC1-independent in podocytes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Bork, T. et al. Podocytes maintain high basal levels of autophagy independent of mtor signaling. Autophagy https://doi.org/10.1080/15548627.2019.1705007 (2019). source

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    Premisecitation

    At 8 weeks, Tek-Atg5−/− mice have lobular capillaries, thickened loops, mesangial matrix expansion, and die by 12 weeks, potentially from severe haematopoietic injury.

    “at 8 weeks of age, the capillaries of Tek–Atg5−/− mice had a lobular pattern, with thickening of the capillary loops and mesangial matrix expansion, and they died by 12 weeks of age, potentially owing to severe haematopoietic injury”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Matsuda, J. et al. Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries. Autophagy 14, 53–65 (2018). source

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    Interpretationcitation

    The inhibitory effect of mTORC1 on podocyte autophagy is limited to a short-term adaptive response, and AMPK signalling is the main regulatory pathway controlling podocyte autophagy.

    “These findings suggest that the inhibitory effect of mTORC1 on podocyte autophagy is limited to a short-term adaptive response and that AMPK signalling is the main regulatory pathway in the control of podocyte autophagy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Bork, T. et al. Podocytes maintain high basal levels of autophagy independent of mtor signaling. Autophagy https://doi.org/10.1080/15548627.2019.1705007 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Endothelial autophagy may protect glomeruli from oxidative stress and maintain glomerular capillary integrity.

    “This observation suggests that endothelial autophagy might protect glomeruli from oxidative stress and maintain the integrity of glomerular capillaries.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Matsuda, J. et al. Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries. Autophagy 14, 53–65 (2018). source

      Not checked in the free run.

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    Premisecitation

    Proteasome activity increases in 8-month-old Atg5−/− mice compared with wild-type and appears to clear protein aggregates and compensate for autophagy loss.

    “Proteasome activity increased in 8-month-old Atg5−/− mice compared with wild-type controls, and this increase seemed to clear protein aggregates and compensate for the loss of autophagy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010). source

      Not checked in the free run.

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    Premisecitation

    Disruption of autophagy in proximal tubules for 24 months causes significant kidney dysfunction, tubular atrophy, and tubulointerstitial fibrosis, accompanied by aggravated ageing-related mitochondrial dysfunction and damage to mitochondrial and nuclear DNA.

    “disruption of autophagy in proximal tubules for 24 months caused significant kidney dysfunction, tubular atrophy and tubulointerstitial fibrosis, which were accompanied by an aggravation of ageing-related mitochondrial dysfunction as well as damage to mitochondrial and nuclear DNA”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016). source

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    Premisecitation

    Aged mouse proximal tubules show dysregulated nutrient sensing pathways, including an ageing-related decline in SIRT1, failure to further activate AMPK in response to starvation, and mTOR hyperactivation.

    “dysregulation of nutrient sensing pathways in the proximal tubules of aged mice, including an ageing-related decline in SIRT1 levels and the failure to further activate AMPK in response to starvation and mTOR hyperactivation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016). source

      Not checked in the free run.

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    Premisecitation

    Podocyte SIRT1 expression is lower in 26-28-month-old mice than in 3-month-old mice, and podocyte-specific Sirt1 knockdown aggravates age-associated kidney injury in ageing mice.

    “podocyte SIRT1 expression was lower in 26–28-month-old mice than in 3-month-old mice and that podocyte-specific knockdown of Sirt1 aggravated age-associated kidney injury in ageing mice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Chuang, P. Y. et al. Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. Am. J. Physiol. Renal Physiol. 313, F621–F628 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Autophagy and apoptosis can be induced by the same stimuli and may share common regulatory molecules enabling them to regulate and modify each other to determine cell fate.

    “autophagy and apoptosis can be induced in response to the same stimuli and these two pathways might share common regulatory molecules enabling them to regulate and modify each other to coordinately determine the fate of the cell”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Proximal tubule epithelial cells of 24-month-old mice have higher basal autophagic flux but a blunted response to starvation-induced autophagy compared with 2-month-old mice.

    “compared with 2-month-old mice, PTECs of 24-month-old mice have a higher basal autophagic flux, but their response to starvation-induced autophagy is blunted”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Podocyte-specific Ctsd−/− mice develop proteinuria at 5 months and kidney failure by 20-22 months.

    “these podocyte-specific Ctsd−/− mice developed proteinuria at 5 months of age and kidney failure by 20–22 months of age”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Yamamoto-Nonaka, K. et al. Cathepsin D in podocytes is important in the pathogenesis of proteinuria and CKD. J. Am. Soc. Nephrol. 27, 2685–2700 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LC3-I and ATG7 expression is dramatically reduced in kidneys of 24-month-old rats compared with 3-month-old animals, accompanied by accumulation of sequestosome 1, ubiquitin-positive aggregates, damaged mitochondria, and oxidative stress.

    “the expression of the autophagy proteins LC3-I and ATG7 was dramatically reduced in the kidneys of 24-month-old rats compared with those of 3-month-old animals, and this decrease was accompanied by an accumulation of sequestosome 1, Ub-positive protein aggregates and damaged mitochondria, as well as the induction of oxidative stress”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Cui, J. et al. Age-related changes in the function of autophagy in rat kidneys. Age 34, 329–339 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured proximal tubule epithelial cells, cisplatin at different doses stimulates distinct unfolded protein response components: 10 μM promotes autophagy, whereas 50 μM induces apoptosis.

    “In cultured PTECs, exposure to cisplatin at different doses stimulated distinct components of the unfolded protein response (UPR) — a 10-μM dose of cisplatin promoted autophagy, whereas a 50-μM dose induced apoptosis”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Rovetta, F. et al. ER signaling regulation drives the switch between autophagy and apoptosis in NRK-52E cells exposed to cisplatin. Exp. Cell Res. 318, 238–250 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ageing is associated with structural and functional kidney changes that may compromise repair capacity and increase susceptibility to damage, potentially underlying high chronic kidney disease incidence in elderly individuals.

    “Ageing is associated with structural and functional changes in the kidney that potentially compromise its capacity for repair and increase its susceptibility to damage — such effects might underlie the high incidence of chronic kidney disease (CKD) in elderly individuals”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] O’Sullivan, E. D., Hughes, J. & Ferenbach, D. A. Renal aging: causes and consequences. J. Am. Soc. Nephrol. 28, 407–420 (2017). source

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  • May combine two claims.

    Interpretationcitation

    Autophagy impairment accelerates the ageing process and tubular damage in young mice.

    “These findings further suggested that autophagy impairment accelerated the ageing process and tubular damage in young mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Liu, S. et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8, 826–837 (2012). source

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  • May combine two claims.

    Premisecitation

    Ageing is accompanied by reduced CEBPα expression, and podocyte-specific CEBPα deletion accelerates kidney ageing with increased senescence markers and ageing-induced kidney lesions compared with wild-type.

    “ageing was accompanied by a reduction in the expression of CCAAT/enhancer-binding protein-α (CEBPα) and that podocyte-specific deletion of CEBPα accelerated kidney ageing, as indicated by the increased accumulation of senescence markers and ageing-induced kidney lesions in Cebpa-knockout mice compared with wild-type controls”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Zhang, L. et al. C/EBPalpha deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice. Cell Death Dis. 10, 684 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In tamoxifen-inducible proximal tubule-specific Atg5 deletion, sequestosome 1 and ubiquitin-positive aggregates accumulate at higher levels in aged kidneys than in younger mice, suggesting aged kidneys are more reliant on autophagy for removal of damaged proteins and organelles.

    “sequestosome 1 and Ub-positive aggregates accumulated at higher levels in aged kidneys than in those from younger mice, suggesting that aged kidneys are more reliant on autophagy for the removal of damaged proteins and organelles”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Ageing-related changes in SIRT1 and CEBPα expression may lead to reduced autophagy in podocytes and promote kidney ageing.

    “These findings suggest that ageing-related changes in the expression of proteins such as SIRT1 and CEBPα might lead to reduced autophagy in podocytes and promote kidney ageing.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Chuang, P. Y. et al. Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. Am. J. Physiol. Renal Physiol. 313, F621–F628 (2017). source

      Not checked in the free run.

    • cites [67] Zhang, L. et al. C/EBPalpha deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice. Cell Death Dis. 10, 684 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Autophagy is active in kidney tubular cells and functions as a defence mechanism in acute kidney injury.

    “current evidence suggests that autophagy is active in kidney tubular cells and functions as a defence mechanism in AKI”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Kaushal, G. P. & Shah, S. V. Autophagy in acute kidney injury. Kidney Int. 89, 779–791 (2016). source

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  • The quote only partly states this claim.

    Premisecitation

    Autophagy and/or mitophagy are protective in sepsis-induced acute kidney injury caused by caecal ligation and puncture or lipopolysaccharide exposure.

    “The beneficial effect of autophagy was further confirmed in two experimental models of sepsis-induced AKI caused by caecal ligation and puncture, or lipopoly-saccharide exposure”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [72] Hsiao, H. W. et al. The decline of autophagy contributes to proximal tubular dysfunction during sepsis. Shock 37, 289–296 (2012). source

      Not checked in the free run.

    • cites [73] Leventhal, J. S. et al. Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression. PloS One 11, e0150001 (2016). source

      Not checked in the free run.

    • cites [74] Mei, S. et al. Autophagy is activated to protect against endotoxic acute kidney injury. Sci. Rep. 6, 22171 (2016). source

      Not checked in the free run.

    • cites [75] Howell, G. M. et al. Augmenting autophagy to treat acute kidney injury during endotoxemia in mice. PloS One 8, e69520 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, adriamycin induces premature senescence in podocytes, accompanied by reduced phospho-AMPK and increased phospho-mTOR; CEBPα overexpression restores dysregulated AMPK and mTOR activity.

    “In vitro, exposure to adriamycin induced premature senescence in podocytes, which was accompanied by a reduction in phospho–AMPK and an increase in phospho–mTOR — overexpression of CEBPα restored the dysregulated activity of AMPK and mTOR”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Zhang, L. et al. C/EBPalpha deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice. Cell Death Dis. 10, 684 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In proximal tubule epithelial cells treated with 50 μM cisplatin, inhibition of autophagy enhances caspase 3, 6, and 7 activity, whereas key autophagy proteins beclin 1, ATG5, and ATG12 are cleaved and degraded in a caspase-dependent manner.

    “in PTECs treated with 50 μM of cisplatin, inhibition of autophagy enhanced the activity of caspases 3, 6 and 7, whereas key autophagy proteins, such as beclin 1, ATG5 and ATG12 were cleaved and degraded in a caspase-dependent manner”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Herzog, C., Yang, C., Holmes, A. & Kaushal, G. P. zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function. Am. J. Physiol. Renal Physiol. 303, F1239–F1250 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mitophagy-mediated elimination of dysfunctional mitochondria may prevent excessive ROS accumulation, activation of the mitochondrial apoptotic cascade, and release of mitochondrial DNA and other damage-associated molecular patterns that promote inflammation during acute kidney injury.

    “The mitophagy-mediated elimination of dysfunctional mitochondria might prevent excessive ROS accumulation and the activation of the mitochondrial apoptotic cascade, as well as inhibit the release of mitochondrial DNA and other damage-associated molecular patterns that might otherwise promote inflammation during AKI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a rat model of ischaemic acute kidney injury, ischaemic preconditioning protection is mediated by autophagy and regulated by an SGK1-FOXO3a-HIF1α signalling axis.

    “in a rat model of ischaemic AKI, IPC protection was mediated by autophagy and regulated by a signalling pathway that involved a serine/threonine protein kinase SGK1–FOXO3a–hypoxia-inducible factor 1α (HIF1α) signalling axis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Xie, Y. et al. Ischemic preconditioning attenuates ischemia/reperfusion-induced kidney injury by activating autophagy via the SGK1 signaling pathway. Cell Death Dis. 9, 338 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Pink1 and/or Park2-knockout mice have more severe kidney dysfunction and tissue damage after ischaemic acute kidney injury, with accumulation of damaged mitochondria, increased tubular cell death, ROS generation, and kidney inflammation, suggesting mitophagy protects tubular cells during ischaemic acute kidney injury.

    “Pink1 and/or Park2-knockout mice had more severe kidney dysfunction and tissue damage, which were accompanied by an accumulation of damaged mitochondria and increased tubular cell death, ROS generation and kidney inflammation, which suggested an important role for mitophagy in the protection of tubular cells during ischaemic AKI”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Tang, C. et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 14, 880–897 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caloric restriction preconditioning stimulates autophagy in kidneys, potentially by increasing SIRT1 expression, preventing decreases in PGC1α and endothelial nitric oxide synthase in kidney tubules, leading to renoprotection.

    “preconditioning with caloric restriction stimulated autophagy in kidneys, potentially by increasing SIRT1 expression, which prevented the decrease in peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) and endothelial nitric oxide synthase in kidney tubules, leading to renoprotection”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Lempiainen, J. et al. Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1alpha-eNOS pathway and enhanced autophagy. Acta Physiol. 208, 410–421 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autophagy has a major role in mediating the renoprotective effects of caloric restriction against kidney ischaemia-reperfusion injury in rats.

    “One study suggested that autophagy has a major role in mediating the renoprotective effects of caloric restriction against kidney IRI in rats.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Lempiainen, J. et al. Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1alpha-eNOS pathway and enhanced autophagy. Acta Physiol. 208, 410–421 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of Pink1 or Park2 in mice abolishes contrast-induced mitophagy in kidney tubules and worsens kidney injury as assessed by tubular damage, plasma creatinine, BUN, mitochondrial damage, ROS production, and cell death.

    “deletion of Pink1 or Park2 in mice abolished contrast-induced mitophagy in kidney tubules and worsened kidney injury as assessed by kidney tubular damage, plasma creatinine and BUN, mitochondrial damage, ROS production and cell death”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Lin, Q. et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 26, 101254 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ischaemic preconditioning is a potential approach for tissue protection during subsequent ischaemic injury in various organs including the kidney, although it seems less effective in aged kidneys.

    “Ischaemic preconditioning (IPC) is a potential approach for tissue protection during subsequent ischaemic injury in various organs including the kidney, although it seems to be less effective in aged kidneys”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Jankauskas, S. S. et al. The age-associated loss of ischemic preconditioning in the kidney is accompanied by mitochondrial dysfunction, increased protein acetylation and decreased autophagy. Sci. Rep. 7, 44430 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured proximal tubule epithelial cells, knockdown of Pink1 or Park2 prevents mitophagy in response to contrast media, and this reduction enhances cell death by activating the NLRP3 inflammasome.

    “In cultured PTECs, knockdown of Pink1 or Park2 prevented the induction of mitophagy in response to contrast media and this reduction in mitophagy enhanced PTEC death by activating the NLRP3 inflammasome”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Lin, Q. et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 26, 101254 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse model of unilateral kidney IRI injury, ER stress and autophagy are both induced in kidney tubular cells.

    “In a mouse model of unilateral kidney IRI injury, ER stress and autophagy were both induced in kidney tubular cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Shu, S. et al. Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease. EBioMedicine 37, 269–280 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TASCC disruption after kidney injury reduces pro-fibrotic cytokine synthesis and secretion in PTECs and suppresses kidney fibrosis after severe AKI.

    “Notably, TASCC disruption after kidney injury reduced the synthesis and secretion of pro-fibrotic cytokines in PTECs and suppressed kidney fibrosis after severe AKI104.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Canaud, G. et al. Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair. Sci. Transl. Med. 11, eaav4754 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Atg5 deletion in the S3 segment inhibits tubular senescence, attenuates interstitial fibrosis, and improves kidney function as assessed by transcutaneous GFR, suggesting autophagy in tubular cells contributes to post-ischaemic kidney fibrosis by promoting senescence.

    “Atg5 deletion in the S3 segment inhibited tubular senescence, attenuated interstitial fibrosis and improved kidney function as assessed by transcutaneous measurement of the glomerular filtration rate, which suggested that autophagy in tubular cells contributed to post-ischaemic kidney fibrosis by promoting senescence”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After acute kidney injury, surviving tubular cells proliferate, migrate, and differentiate to replace lost tubular cells and repair injured kidney tubules.

    “After AKI, surviving tubular cells proliferate, migrate and then differentiate to replace lost tubular cells and repair injured kidney tubules”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Chang-Panesso, M. et al. FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury. J. Clin. Invest. 129, 5501–5517 (2019). source

      Not checked in the free run.

    • cites [95] Kusaba, T., Lalli, M., Kramann, R., Kobayashi, A. & Humphreys, B. D. Differentiated kidney epithelial cells repair injured proximal tubule. Proc. Natl Acad. Sci. USA 111, 1527–1532 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Cyclin G1 promotes G2/M arrest in PTECs and upregulates TASCC formation.

    “Cyclin G1 promoted G2/M arrest in PTECs and upregulated TASCC formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Compared with wild-type littermates, Atg5-knockout mice have more tubular cell death 2 h after reperfusion but reduced tubular damage and inflammation at day 3, suggesting autophagy enhances cell survival during initial tubular injury but hinders normal repair during recovery.

    “compared with wild-type littermates, Atg5-knockout mice had more tubular cell death 2 h after reperfusion, but reduced tubular damage and inflammation at day 3, suggesting that autophagy enhances cell survival during the initial tubular injury but hinders normal repair during the recovery phase”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In autophagy-reporter mice expressing RFP-EGFP-LC3, autophagy is induced in proximal tubules 1 day after reperfusion, and at day 3 autophagosomes fuse with lysosomes for clearance, leading to resolution of autophagy.

    “autophagy was induced in proximal tubules 1 day after reperfusion and that at day 3 autophagosomes fused with lysosomes for clearance, leading to the resolution of autophagy in those cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Li, L., Wang, Z. V., Hill, J. A. & Lin, F. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. J. Am. Soc. Nephrol. 25, 305–315 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following ischaemic acute kidney injury, persistent activation of autophagy and pro-senescent changes occur in S3 segments of proximal tubules, along with kidney fibrosis.

    “Following ischaemic AKI, researchers observed persistent activation of autophagy and pro-senescent changes in the S3 segments of proximal tubules, as well as kidney fibrosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proximal tubule-specific Atg5-knockout impairs hyperuricaemia-induced lysophagy in kidney tubules and aggravates hyperuricaemia-induced kidney injury as assessed by plasma creatinine and BUN.

    “Proximal tubule-specific Atg5-knockout impaired hyperuricaemia-induced lysophagy in kidney tubules and aggravated hyperuricaemia-induced kidney injury as assessed by plasma creatinine and BUN”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kidney ischaemia-reperfusion injury causes comparable injury at day 1 in wild-type and telomerase (TerC or TerT)-knockout mice, but wild-type mice recover 2-3 days after injury and restore kidney function within 14 days, whereas knockout mice have delayed and incomplete recovery.

    “Kidney IRI caused comparable kidney injury at day 1 in both wild-type and telomerase (TerC or TerT)-knockout mice, but whereas wild-type mice showed kidney recovery 2–3 days after IRI and kidney function, as assessed by plasma creatinine and BUN, was restored to normal within 14 days, knockout mice had delayed and incomplete kidney recovery”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Cheng, H., Fan, X., Lawson, W. E., Paueksakon, P. & Harris, R. C. Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy. Kidney Int. 88, 85–94 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tubular repair may be complete after mild acute kidney injury, but severe or episodic acute kidney injury are usually followed by incomplete or maladaptive repair that results in kidney fibrosis and chronic kidney disease.

    “Tubular repair might be complete after mild AKI, but severe or episodic AKI are usually followed by incomplete or maladaptive repair that results in the development of kidney fibrosis and CKD”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] Rosen, S. & Heyman, S. Concerning cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int. 94, 218 (2018). source

      Not checked in the free run.

    • cites [97] Kumar, S. Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int. 93, 27–40 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared with wild-type mice, in which autophagy is initiated at day 1 after reperfusion, peaks at day 3, and reduces gradually within 7-14 days, proximal tubule-specific telomerase-knockout mice show no induction of autophagy as late as 14 days after reperfusion.

    “compared with wild-type mice, in which autophagy was initiated at day 1 after reperfusion, peaked at day 3 and then reduced gradually within 7–14 days, proximal tubule-specific telomerase-knockout mice showed no induction of autophagy as late as 14 days after reperfusion”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Cheng, H., Fan, X., Lawson, W. E., Paueksakon, P. & Harris, R. C. Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy. Kidney Int. 88, 85–94 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interstitial fibrosis is a hallmark of maladaptive repair in the acute kidney injury-to-chronic kidney disease transition, and autophagy may have a pro-fibrotic role according to a mouse model of post-ischaemic kidney fibrosis.

    “Interstitial fibrosis is a hallmark of maladaptive repair in the transition from AKI to CKD (FIG. 4) and autophagy might also have a pro-fibrotic role according to findings from a mouse model of post-ischaemic kidney fibrosis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both autophagy and apoptosis promote tubular atrophy and nephron loss in UUO.

    “both pathways promoted tubular atrophy and nephron loss107”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Li, L., Zepeda-Orozco, D., Black, R. & Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767–1778 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of mTOR in some proximal tubule cells leads to persistent activation of autophagy and impaired proliferation, indicating mTOR activation contributes to resolution of autophagy and tubular repair.

    “The inhibition of mTOR in some proximal tubule cells led to persistent activation of autophagy and impaired proliferation, which indicated that mTOR activation contributed to the resolution of autophagy and tubular repair.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [98] Li, L., Wang, Z. V., Hill, J. A. & Lin, F. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. J. Am. Soc. Nephrol. 25, 305–315 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Foxo3-knockout mice, BNIP3 expression is decreased, whereas ULK1 expression is only slightly reduced.

    “The expression of BNIP3, a known target of FOXO3 and a key component of the autophagy machinery, was also decreased in Foxo3-knockout mice, whereas ULK1 expression was only slightly reduced.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Li, L. et al. FoxO3 activation in hypoxic tubules prevents chronic kidney disease. J. Clin. Invest. 129, 2374–2389 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice subjected to UUO, autophagy is induced along with apoptosis in obstructed kidney tubules.

    “Earlier studies showed that, in mice subjected to UUO, autophagy was induced along with apoptosis in obstructed kidney tubules”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Li, L., Zepeda-Orozco, D., Black, R. & Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767–1778 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    After severe kidney injury, TASCC formation begins at day 7, increases remarkably between days 14 and 21 as fibrosis progresses, and is sustained at a moderate level at day 42.

    “Of note, TASCC formation began 7 days after injury, increased remarkably between days 14 and 21 as kidney fibrosis progressed, and was sustained at a moderate level at day 42, which was the experimental end point.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Map1s deletion impairs autophagic clearance of fibronectin and induces kidney fibrosis in aged mice.

    “Map1s deletion impaired autophagic clearance of fibronectin and induced kidney fibrosis in aged mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Xu, G. et al. Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging 8, 977–985 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following UUO, FOXO3 is activated and expressed in nuclei of autophagic proximal tubules.

    “Following UUO, FOXO3 was activated and expressed in the nuclei of autophagic proximal tubules”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Li, L. et al. Forkhead box O3 (FoxO3) regulates kidney tubular autophagy following urinary tract obstruction. J. Biol. Chem. 292, 13774–13783 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kidney biopsy samples from patients with kidney fibrosis show reduced MAP1S expression and fibronectin accumulation compared with normal kidney tissues distant from tumour foci in clear cell renal cell carcinoma.

    “The researchers also observed reduced expression of MAP1S and accumulation of fibronectin in kidney biopsy samples from patients with kidney fibrosis compared with normal kidney tissues distant from tumour foci collected from patients with clear cell renal cell carcinoma117.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Xu, G. et al. Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging 8, 977–985 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of autophagy by chloroquine or selective deletion of Atg7 in proximal tubules reduces kidney fibrosis in UUO mice compared with controls.

    “Importantly, inhibition of autophagy by chloroquine, or by selective deletion of Atg7 in proximal tubules, reduced kidney fibrosis in UUO mice compared with untreated or wild-type controls, respectively”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Livingston, M. J. et al. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy 12, 976–998 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In UUO mice and cultured kidney fibroblasts exposed to TGFβ1, autophagy has pro-fibrotic effects and is involved in activation of kidney fibroblasts.

    “One study in UUO mice and in cultured kidney fibroblast cells exposed to TGFβ1 suggested that autophagy has pro-fibrotic effects and is involved in the activation of kidney fibroblasts112.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Xue, X. et al. Protein kinase Calpha drives fibroblast activation and kidney fibrosis by stimulating autophagic flux. J. Biol. Chem. 293, 11119–11130 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the kidney, autophagy might have a pro-fibrotic effect by promoting lipid accumulation and lipotoxicity in tubular cells, and by stimulating lipolysis to fuel liver fibroblasts.

    “In the kidney, autophagy might have a pro-fibrotic effect by promoting the accumulation of lipids and inducing lipotoxicity in kidney tubular cells, as well as stimulating lipolysis to fuel liver fibroblasts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In mouse models of liver fibrosis induced by thioacetamide or carbon tetrachloride, autophagy induction in hepatic stellate cells leads to lipid degradation and activates these cells to promote liver fibrosis.

    “Interestingly, in mouse models of liver fibrosis induced by thioacetamide or carbon tetrachloride, the induction of autophagy in hepatic stellate cells led to lipid degradation and activated these cells to promote liver fibrosis110,111.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [110] Hernandez-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938–946 (2012). source

      Not checked in the free run.

    • cites [111] Thoen, L. F. et al. A role for autophagy during hepatic stellate cell activation. J. Hepatol. 55, 1353–1360 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prohibitin 2-mediated mitophagy is induced by angiotensin II and attenuates kidney tubular cell injury by improving mitochondrial function and inhibiting NLRP3 inflammasome activation.

    “Moreover, prohibitin 2-mediated mitophagy was induced by angiotensin II and attenuated kidney tubular cell injury by improving mitochondrial function and inhibiting NLRP3 inflammasome activation121.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Xu, Y., Wang, J., Xu, W., Ding, F. & Ding, W. Prohibitin 2-mediated mitophagy attenuates renal tubular epithelial cells injury by regulating mitochondrial dysfunction and NLRP3 inflammasome activation. Am. J. Physiol. Renal Physiol. 316, F396–F407 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In UUO mice, pharmacological inhibition of autophagy markedly reduces lipid accumulation in kidney tubules, accompanied by reduced tubular cell apoptosis and degeneration, and suppresses kidney interstitial fibrosis.

    “In addition, in UUO mice, pharmacological inhibition of autophagy markedly reduced the accumulation of lipids in kidney tubules, which was accompanied by reduced tubular cell apoptosis and degeneration, and suppressed kidney interstitial fibrosis109.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Yan, Q. et al. Autophagy activation contributes to lipid accumulation in tubular epithelial cells during kidney fibrosis. Cell Death Discov. 4, 2 (2018).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured mouse PTECs, MAP1S interacts with LC3 and activates autophagy, contributing to suppression of fibrosis by increasing fibronectin turnover.

    “In cultured mouse PTECs, microtubule associated protein 1 S (MAP1S) interacted with LC3 and activated autophagy, which contributed to the suppression of fibrosis by increasing fibronectin turnover117.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Xu, G. et al. Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis. Aging 8, 977–985 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atg5 overexpression elevates autophagy in angiotensin II-treated PTECs and is accompanied by reduction in cells arrested in G2/M phase and collagen 1 expression.

    “Moreover, Atg5 overexpression elevated autophagy in angiotensin II-treated PTECs accompanied by a reduction in cells arrested in the G2/M phase and collagen 1 expression119.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Li, H. et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy 12, 1472–1486 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a mouse kidney podocyte cell line, exposure to high glucose for 48 h induces autophagy, whereas exposure for 15 days suppresses autophagy.

    “In a mouse kidney podocyte cell line, exposure to high glucose for 48 h induced autophagy, whereas exposure to high glucose for 15 days had a suppressive effect on autophagy60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Lenoir, O. et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11, 1130–1145 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGRN is significantly reduced in kidneys of STZ-induced diabetic mice and in kidney biopsy samples from patients with DKD compared with controls.

    “PGRN was significantly reduced in kidneys of STZ-induced diabetic mice and in kidney biopsy samples from patients with DKD compared with control mice and healthy human tissue, respectively135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Zhou, D. et al. PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell Death Dis. 10, 524 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of FOXO1 in podocytes activates PINK1-parkin-dependent mitophagy, eliminates aberrant mitochondria and ameliorates podocyte injury in STZ-induced diabetic mice.

    “In addition, overexpression of FOXO1 in podocytes activated PINK1–parkin-dependent mitophagy, which eliminated aberrant mitochondria and ameliorated podocyte injury in STZ-induced diabetic mice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Li, W. et al. FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/Parkin pathway. Endocrinology 158, 2155–2167 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In STZ-induced type 1 diabetic mice, podocyte autophagy is induced at 4 weeks and suppressed at 8 weeks post-STZ injection.

    “In line with these in vitro findings, in streptozotocin (STZ)-induced type 1 diabetic mice, podocyte autophagy was induced at 4 weeks and suppressed at 8 weeks post-STZ injection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Lenoir, O. et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11, 1130–1145 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with antioxidants resveratrol and vitamin E restores lysosomal function and rescues impairment in autophagy, thereby attenuating AGE-induced podocyte injury.

    “Treatment with the antioxidants resveratrol and vitamin E restored lysosomal function and rescued the impairment in autophagy, thereby attenuating AGE-induced podocyte injury.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Liu, W. J. et al. Lysosome restoration to activate podocyte autophagy: a new therapeutic strategy for diabetic kidney disease. Cell Death Dis. 10, 806 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DKD is one of the most common and life-threatening diabetic complications and a leading cause of CKD and kidney failure worldwide.

    “Diabetic kidney disease (DKD) is one of the most common and life-threatening diabetic complications and a leading cause of CKD and kidney failure worldwide126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Alicic, R. Z., Rooney, M. T. & Tuttle, K. R. Diabetic kidney disease: challenges, progress, and possibilities. Clin. J. Am. Soc. Nephrol. 12, 2032–2045 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exposure to recombinant PGRN promotes mitophagy and mitochondrial biogenesis, thereby attenuating podocyte injury in diabetic mice.

    “whereas exposure to recombinant PGRN promoted mitophagy and mitochondrial biogenesis, thereby attenuating podocyte injury in diabetic mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Zhou, D. et al. PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell Death Dis. 10, 524 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β-Arrestins are upregulated in kidneys of patients and mice with diabetes compared with healthy counterparts, and in podocytes exposed to high glucose.

    “β-Arrestins, which were upregulated in the kidneys of patients and mice with diabetes compared with their healthy counterparts, as well as in podocytes exposed to high glucose”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Liu, J. et al. beta-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy. Cell Death Dis. 7, e2183 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β-Arrestins interact with ATG7 and negatively regulate ATG12-ATG5 conjugation, suppressing autophagy in podocytes.

    “β-Arrestins interacted with ATG7 and negatively regulated ATG12–ATG5 conjugation, which suppressed autophagy in podocytes132.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Liu, J. et al. beta-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy. Cell Death Dis. 7, e2183 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Short-term exposure of podocytes to hyperglycaemia in vitro or early stages of diabetes might induce autophagy for renoprotection, whereas prolonged hyperglycaemia in vitro or late stages of diabetes might suppress podocyte autophagy and contribute to DKD progression.

    “These results suggest that exposure of podocytes to hyperglycaemia, either short-term exposure in vitro or in the early stages of diabetes, might induce autophagy for renoprotection, whereas prolonged hyperglycaemia in vitro or in the late stages of diabetes, might suppress autophagy in podocytes and contribute to the progression of DKD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The pathological hallmark of DKD is persistent albuminuria or proteinuria accompanied by decline of glomerular filtration rate and pathological changes in all kidney compartments.

    “The pathological hallmark of DKD is persistent albuminuria or proteinuria accompanied by the decline of the glomerular filtration rate and pathological changes in all kidney compartments126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Alicic, R. Z., Rooney, M. T. & Tuttle, K. R. Diabetic kidney disease: challenges, progress, and possibilities. Clin. J. Am. Soc. Nephrol. 12, 2032–2045 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Podocyte autophagy is impaired in patients with type 2 diabetes and in OLETF rats with severe proteinuria, but not in those with no or minimal proteinuria.

    “Another study showed that podocyte autophagy was impaired in patients with type 2 diabetes, as well as in OLETF rats (that is, rats with obesity-induced diabetes), with severe proteinuria, but not in those with no or minimal proteinuria128.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Tagawa, A. et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65, 755–767 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HDAC4 inhibition restores autophagy and ameliorates podocyte injury.

    “HDAC4 inhibition restored autophagy and ameliorated podocyte injury133.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Wang, X. et al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int. 86, 712–725 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    In DKD, alterations in podocyte autophagy seem to correlate with duration of exposure to hyperglycaemia, severity of podocyte injury and glomerulopathy, and disease stage or severity of DKD.

    “In DKD, alterations in podocyte autophagy seem to correlate with the duration of the exposure to hyperglycaemia, the severity of podocyte injury and glomerulopathy, and disease stage or severity of DKD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The UUO model is not ideal for studying kidney repair because fibrosis progresses rapidly, is irreversible, and the injury phase cannot be easily distinguished from the repair phase.

    “Of note, the UUO model is not ideal for the study of kidney repair, as fibrosis progresses rapidly, is irreversible and the injury phase cannot be easily distinguished from the repair phase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SHPS1/SIRPα is reduced in podocytes from STZ-induced diabetic mice and in cultured podocytes treated with high glucose.

    “SHPS1 was reduced in podocytes from STZ-induced diabetic mice and in cultured podocytes treated with high glucose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Li, L. et al. Signal regulatory protein alpha protects podocytes through promoting autophagic activity. JCI Insight 5, e124747 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under these conditions, HDAC4 suppresses podocyte autophagy by deacetylating STAT1 and sensitizes podocytes to injury.

    “Under these conditions, HDAC4 suppressed podocyte autophagy by deacetylating STAT1 and sensitized podocytes to injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Wang, X. et al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int. 86, 712–725 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A high-fat diet induces minimal proteinuria in wild-type mice, but podocyte-specific Atg5-knockout mice develop substantial albuminuria accompanied by severe tubulointerstitial lesions and podocyte injury with damaged lysosomes.

    “Moreover, a high-fat diet induced minimal proteinuria in wild-type mice, but podocyte-specific Atg5-knockout mice developed substantial albuminuria accompanied by severe tubulointerstitial lesions and injury to podocytes, which accumulated damaged lysosomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Tagawa, A. et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65, 755–767 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGRN-related mitochondrial protection is mediated via PGRN-SIRT1-PGC1α regulation of FOXO1 and can be abrogated by inhibition of mitophagy.

    “PGRN-related mitochondrial protection was mediated via PGRN–SIRT1–PGC1α regulation of FOXO1 and could be abrogated by the inhibition of mitophagy135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Zhou, D. et al. PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell Death Dis. 10, 524 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulating cultured podocytes with serum from patients with type 2 diabetes or OLETF rats with severe proteinuria inhibits autophagy and induces lysosomal dysfunction and apoptosis.

    “Interestingly, stimulating cultured podocytes with serum from patients with type 2 diabetes or OLETF rats with severe proteinuria inhibited autophagy and induced lysosomal dysfunction and apoptosis”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Tagawa, A. et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65, 755–767 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pgrn deficiency aggravates mitochondrial damage and dysfunction in podocytes from diabetic mice and worsens podocyte injury and proteinuria.

    “Pgrn deficiency aggravated mitochondrial damage and dysfunction in podocytes from diabetic mice and worsened podocyte injury and proteinuria”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Zhou, D. et al. PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy. Cell Death Dis. 10, 524 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At 4 weeks after STZ injections, mice are only hyperglycaemic and do not have glomerular lesions; podocyte injury is present at 8 weeks.

    “Of note, 4 weeks after STZ injections these mice were only hyperglycaemic and did not have glomerular lesions; however, podocyte injury was present at the 8-week time point.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Lenoir, O. et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11, 1130–1145 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inositol oxygenase is upregulated in PTECs exposed to high glucose and in kidney tubules of diabetic mice; mitochondrial fragmentation and reduction in mitophagy are also observed.

    “Inositol oxygenase (encoded by Miox) was upregulated in PTECs exposed to high glucose and in the kidney tubules of diabetic mice; mitochondrial fragmentation and reduction in mitophagy were also observed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Zhan, M., Usman, I. M., Sun, L. & Kanwar, Y. S. Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. J. Am. Soc. Nephrol. 26, 1304–1321 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy impairment in these conditions is mediated by p53-miR-214-ULK1 axis, where p53 is activated in DKD to induce miR-214 in kidney tubules, and miR-214 directly targets ULK1.

    “Importantly, autophagy impairment in these conditions was shown to be mediated by the p53–microRNA (miR)-214–ULK1 axis, where p53 is activated in DKD to induce miR-214 in kidney tubules. Upon induction, miR-214 directly targets ULK1, leading to autophagy impairment140.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Ma, Z. et al. p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney. J. Clin. Invest. (in the press).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In diabetic Wistar fatty rats, impaired autophagy in PTECs is reversed by a very-low-protein diet and by daily 40% restriction of food consumption, which suppress mTORC1 and activate SIRT1 pathways, respectively.

    “Similarly, in diabetic Wistar fatty rats, impaired autophagy in PTECs was reversed by a very-low-protein diet and by a daily 40% restriction of the food consumption, which suppressed mTORC1 and activated SIRT1 pathways, respectively”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [152] Kitada, M. et al. Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp. Diabetes Res. 2011, 908185 (2011). source

      Not checked in the free run.

    • cites [153] Kitada, M. et al. A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. Diabetologia 59, 1307–1317 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These interventions attenuate DKD-related tubular injury and kidney dysfunction.

    “resulting in an attenuation of DKD-related tubular injury and kidney dysfunction152,153.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [152] Kitada, M. et al. Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp. Diabetes Res. 2011, 908185 (2011). source

      Not checked in the free run.

    • cites [153] Kitada, M. et al. A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. Diabetologia 59, 1307–1317 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High-glucose conditions seem to lead to defective autophagy, lysosomal dysfunction and accumulation of AGEs in PTECs.

    “but high-glucose conditions seem to lead to defective autophagy, lysosomal dysfunction and the accumulation of AGEs in PTECs.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Takahashi, A. et al. Autophagy inhibits the accumulation of advanced glycation end products by promoting lysosomal biogenesis and function in the kidney proximal tubules. Diabetes 66, 1359–1372 (2017). source

      Not checked in the free run.

    • cites [157] Liu, W. J. et al. Autophagy-lysosome pathway in renal tubular epithelial cells is disrupted by advanced glycation end products in diabetic nephropathy. J. Biol. Chem. 290, 20499–20510 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Prolonged or excessive albumin uptake might eventually impair autophagy in PTECs through an mTOR-dependent mechanism and induce progressive tubular injury.

    “However, prolonged or excessive albumin uptake might eventually impair autophagy in PTECs through an mTOR-dependent mechanism and induce progressive tubular injury150.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] Nolin, A. C. et al. Proteinuria causes dysfunctional autophagy in the proximal tubule. Am. J. Physiol. Renal Physiol. 311, F1271–F1279 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of optineurin but not PINK1 restores mitophagy and protects PTECs against premature senescence and NLRP3 inflammasome activation, attenuating tubular injury.

    “Overexpression of optineurin but not of PINK1 restored mitophagy and protected PTECs against premature senescence and activation of the NLRP3 inflammasome, which attenuated tubular injury145.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Chen, K. et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis. 9, 105 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy is impaired in high glucose-treated PTECs, diabetic kidneys of mice and kidney biopsy samples from patients with DKD.

    “One study reported that autophagy was impaired in high glucose-treated PTECs, diabetic kidneys of mice and kidney biopsy samples from patients with DKD140.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Ma, Z. et al. p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney. J. Clin. Invest. (in the press).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High glucose causes defective mitophagy in PTECs and accelerates tubular cell senescence.

    “High glucose also caused defective mitophagy in PTECs and accelerated tubular cell senescence.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Chen, K. et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis. 9, 105 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In diabetic PTECs, deacetylation of TFEB by HDAC6 suppresses activity and nuclear localization of TFEB, leading to inhibition of autophagy and tubular cell death.

    “In diabetic PTECs, deacetylation of TFEB by HDAC6 suppressed the activity and nuclear localization of this transcription factor, which led to the inhibition of autophagy and tubular cell death146.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Brijmohan, A. S. et al. HDAC6 inhibition promotes transcription factor EB activation and is protective in experimental kidney disease. Front. Pharmacol. 9, 34 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Hyperglycaemia inhibits autophagy in kidney tubules and different signalling pathways are involved in this effect.

    “Collectively, these results suggest that hyperglycaemia inhibits autophagy in kidney tubules and that different signalling pathways are involved in this effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Pretreatment with rapamycin causes stagnation of autophagy and exaggerates kidney IRI in STZ-injected mice, whereas rapamycin reactivates autophagy and attenuates kidney IRI in db/db mice.

    “Notably, pretreatment with rapamycin caused stagnation of autophagy and exaggerated kidney IRI in STZ-injected mice, whereas rapamycin reactivated autophagy and attenuated kidney IRI in db/db mice154.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Sakai, S. et al. Proximal tubule autophagy differs in type 1 and 2 diabetes. J. Am. Soc. Nephrol. 30, 929–945 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological inhibition of Lys63-Ub induced by high glucose significantly rescues autophagy impairment in PTECs and abrogates tubular cell apoptosis.

    “Pharmacological inhibition of Lys63–Ub induced by high glucose significantly rescued autophagy impairment in PTECs and consequently abrogated tubular cell apoptosis147.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Pontrelli, P. et al. Deregulation of autophagy under hyperglycemic conditions is dependent on increased lysine 63 ubiquitination: a candidate mechanism in the progression of diabetic nephropathy. J. Mol. Med. 96, 645–659 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of mitochondria-targeted antioxidant MitoQ ameliorates tubular injury in diabetic mice and reduces high-glucose-induced PTEC death by partially restoring mitophagy.

    “Another study demonstrated that administration of the mitochondria-targeted antioxidant MitoQ ameliorated tubular injury in diabetic mice and reduced high-glucose-induced PTEC death by partially restoring mitophagy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Ma, Z. et al. p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney. J. Clin. Invest. (in the press).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of inositol oxygenase reactivates mitophagy and improves mitochondrial integrity.

    “Inhibition of inositol oxygenase reactivated mitophagy and improved mitochondrial integrity139.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Zhan, M., Usman, I. M., Sun, L. & Kanwar, Y. S. Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. J. Am. Soc. Nephrol. 26, 1304–1321 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TXNIP is upregulated in kidney of STZ-induced diabetic rats and in PTECs exposed to high glucose, where it activates mTORC1 and impairs autophagy.

    “Thioredoxin-interacting protein (encoded by TXNIP) was also upregulated in the kidney of STZ-induced diabetic rats and in PTECs exposed to high glucose, where it activated mTORC1 and impaired autophagy144.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Huang, C. et al. Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway. Sci. Rep. 6, 29196 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    Understanding distinct patterns of autophagy dysregulation in PTECs in different types of DKD is crucial to their therapeutic targeting.

    “These results highlight that understanding the distinct patterns of autophagy dysregulation in PTECs in different types of DKD is crucial to their therapeutic targeting.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    SGLT2 is the primary regulator of tubular glucose reabsorption and its expression is upregulated in diabetic kidneys.

    “Sodium–glucose cotransporter 2 (SGLT2) is the primary regulator of tubular glucose reabsorption and its expression is upregulated in diabetic kidneys.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Autophagy is suppressed in db/db mice owing to hyperactive mTOR, whereas high levels of autophagy are induced in STZ-injected mice, which eventually leads to lysosomal stress.

    “Therefore, autophagy was suppressed in db/db mice owing to hyperactive mTOR, whereas high levels of autophagy were induced in STZ-injected mice, which eventually led to lysosomal stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Sakai, S. et al. Proximal tubule autophagy differs in type 1 and 2 diabetes. J. Am. Soc. Nephrol. 30, 929–945 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Timp3 is downregulated in kidney of STZ-induced diabetic mice and in patients with diabetes, as well as in GMCs treated with high glucose.

    “The metalloproteinase inhibitor 3 gene (Timp3) was downregulated in the kidney of STZ-induced diabetic mice and in patients with diabetes, as well as in GMCs treated with high glucose”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Fiorentino, L. et al. Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol. Med. 5, 441–455 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Analysis of repeated kidney biopsies from patients with MCD reveals that patients with reduced podocyte autophagy are more likely to progress to FSGS than patients with relatively high levels of podocyte autophagy, who are more likely to have MCD.

    “An analysis of repeated kidney biopsies from patients with MCD further revealed that patients with reduced podocyte autophagy were more likely to progress to FSGS than patients with relatively high levels of podocyte autophagy, who were more likely to have MCD168.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Zeng, C. et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J. Pathol. 234, 203–213 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy and mitophagy are activated in GMCs via ROS and prevent AGE-induced mitochondrial dysfunction and cell apoptosis.

    “Autophagy and mitophagy were activated in GMCs via ROS and prevented AGE-induced mitochondrial dysfunction and cell apoptosis161.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Xu, L., Fan, Q., Wang, X., Zhao, X. & Wang, L. Inhibition of autophagy increased AGE/ROS-mediated apoptosis in mesangial cells. Cell Death Dis. 7, e2445 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FSGS is a fibrotic kidney disease characterized by glomerular lesions, particularly in podocytes, where adhesions in glomerular capillary tuft lead to capillary occlusion and nephron degeneration.

    “Focal segmental glomerulosclerosis (FSGS) is a fibrotic kidney disease characterized by glomerular lesions, particularly in podocytes — the formation of adhesions in the glomerular capillary tuft leads to capillary occlusion and nephron degeneration162.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Rosenberg, A. Z. & Kopp, J. B. Focal Segmental Glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 12, 502–517 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This vicious cycle might eventually lead to irreversible injury in kidney tubules, glomeruli and tubulointerstitium, contributing to DKD progression.

    “This vicious cycle might eventually lead to irreversible injury in the kidney tubules, glomeruli and tubulointerstitium, contributing to the progression of DKD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    LAMP1 is upregulated in response to AGE overload in Atg5-competent primary PTECs, but is suppressed in ATG5-deficient cells.

    “Lysosome-associated membrane glycoprotein 1 (LAMP1) was upregulated in response to AGE overload in Atg5-competent primary PTECs, but was suppressed in ATG5-deficient cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Takahashi, A. et al. Autophagy inhibits the accumulation of advanced glycation end products by promoting lysosomal biogenesis and function in the kidney proximal tubules. Diabetes 66, 1359–1372 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    FSGS is either idiopathic or secondary to other disorders such as acquired immune deficiency syndrome and obesity; cause of idiopathic FSGS remains unclear.

    “FSGS is either idiopathic or secondary to a number of other disorders, such as acquired immune deficiency syndrome and obesity; the cause of idiopathic FSGS remains unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In PAN treatment of differentiated podocytes and rats to model FSGS, there is a positive correlation between levels of LC3-II and number of autophagic vacuoles in podocytes, as well as recovery from damage induced by PAN nephrosis.

    “Using puromycin aminonucleoside (PAN) treatment of differentiated podocytes and rats to model FSGS, researchers revealed a positive correlation between levels of LC3-II and the number of autophagic vacuoles in podocytes, as well as the recovery from the damage induced by PAN nephrosis165.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Asanuma, K. et al. MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis. FASEB J. 17, 1165–1167 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mechanisms underlying activation of autophagy in FSGS podocytes remain largely unclear, but activation of mTORC1 and downregulation of SIRPα were observed in glomeruli from both patients with FSGS and mouse models of FSGS.

    “The mechanisms underlying the activation of autophagy in FSGS podocytes remain largely unclear, but activation of mTORC1 (REFS166,170) and downregulation of SIRPα138 were observed in glomeruli from both patients with FSGS and in mouse models of FSGS.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [166] Yi, M. et al. Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy. Am. J. Physiol. Renal Physiol. 313, F74–F84 (2017). source

      Not checked in the free run.

    • cites [170] Zschiedrich, S. et al. Targeting mTOR signaling can prevent the progression of FSGS. J. Am. Soc. Nephrol. 28, 2144–2157 (2017). source

      Not checked in the free run.

    • cites [138] Li, L. et al. Signal regulatory protein alpha protects podocytes through promoting autophagic activity. JCI Insight 5, e124747 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of autophagy in podocytes might represent a defence mechanism in FSGS and a potential therapeutic strategy.

    “Activation of autophagy in podocytes might therefore represent a defence mechanism in FSGS and a potential therapeutic strategy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with FSGS have a significantly lower percentage of autophagosome-positive podocytes and significantly lower levels of kidney beclin 1 than patients with MCD.

    “Electron microscopy and biochemical analyses revealed that patients with FSGS had a significantly lower percentage of autophagosome-positive podocytes and significantly lower levels of kidney beclin 1 than patients with minimal change disease (MCD)168.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Zeng, C. et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J. Pathol. 234, 203–213 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, podocyte apoptosis induced by adriamycin is reduced by rapamycin but increased by chloroquine.

    “In vitro, podocyte apoptosis induced by adriamycin was reduced by rapamycin but increased by chloroquine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Yi, M. et al. Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy. Am. J. Physiol. Renal Physiol. 313, F74–F84 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Impaired autophagy in diabetes might reduce clearance of damaged lysosomes and lead to AGE accumulation, which further disrupts lysosomal function.

    “impaired autophagy in diabetes might therefore reduce the clearance of damaged lysosomes and lead to AGE accumulation, which further disrupts lysosomal function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AGEs accumulate in PTECs, glomeruli and kidney vasculature of Atg5-knockout diabetic mice, in which inflammation and kidney fibrosis increase compared with controls.

    “Of note, AGEs also accumulated in the PTECs, glomeruli and kidney vasculature of these Atg5-knockout diabetic mice, in which inflammation and kidney fibrosis increased compared with controls156.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Takahashi, A. et al. Autophagy inhibits the accumulation of advanced glycation end products by promoting lysosomal biogenesis and function in the kidney proximal tubules. Diabetes 66, 1359–1372 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Autophagy in GECs preserves both endothelial integrity and podocyte homeostasis.

    “These observations suggest that autophagy in GECs preserves both endothelial integrity and podocyte homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BAMBI is downregulated in glomeruli isolated from biopsy samples of patients with DKD compared with healthy donors, and in glomeruli of STZ-induced diabetic mice compared with wild-type controls.

    “BAMBI was downregulated in glomeruli isolated from biopsy samples of patients with DKD compared with samples from healthy donors, and in the glomeruli of STZ-induced diabetic mice compared with wild-type controls159.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Fan, Y. et al. BAMBI elimination enhances alternative TGF-beta signaling and glomerular dysfunction in diabetic mice. Diabetes 64, 2220–2233 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Reasons for discrepancies in human autophagy findings remain unknown and highlight complexity of autophagy in human kidney cells, complicating use of autophagy biomarkers to predict progression of kidney diseases.

    “The reasons for these discrepancies remain unknown and highlight the complexity of autophagy in human kidney cells, which complicates the use of autophagy biomarkers to predict the progression of kidney diseases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A 2010 study suggested that autophagy might be involved in regulating degradation of BAMBI in endothelial cells.

    “A 2010 study suggested that autophagy might be involved in regulating the degradation of bone morphogenetic protein and activin membrane bound inhibitor (BAMBI) in endothelial cells158.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Xavier, S. et al. BAMBI is expressed in endothelial cells and is regulated by lysosomal/autolysosomal degradation. PLoS One 5, e12995 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of Atg5 or Atg7 in embryonic nephron progenitor cells causes loss of autophagy in entire nephron sufficient to induce albuminuria, as well as glomerular and tubulointerstitial changes, recapitulating pathological features of human idiopathic FSGS.

    “In another study, researchers deleted Atg5 or Atg7 in embryonic nephron progenitor cells and demonstrated that loss of autophagy in the entire nephron was sufficient to induce albuminuria, as well as glomerular and tubulointerstitial changes, that recapitulated the pathological features of human idiopathic FSGS167.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Kawakami, T. et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J. Am. Soc. Nephrol. 26, 1040–1052 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PKD is the most common genetic form of CKD and is characterized by development and growth of multiple kidney cysts, leading to kidney damage and kidney failure.

    “Polycystic kidney disease (PKD) is the most common genetic form of CKD and is characterized by the development and growth of multiple kidney cysts, which leads to kidney damage and can cause kidney failure171.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [171] Torres, V. E. & Harris, P. C. Progress in the understanding of polycystic kidney disease. Nat. Rev. Nephrol. 15, 70–72 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autophagy inhibitors, including 3-methyladenine and chloroquine, have been widely tested in animal studies.

    “Autophagy inhibitors, including 3-methyladenine and chloroquine, have also been widely tested in animal studies197.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Pasquier, B. Autophagy inhibitors. Cell Mol. Life Sci. 73, 985–1001 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Autophagy has an important role in kidney physiology and pathology, as supported by substantial evidence.

    “Substantial evidence supports an important role for autophagy in kidney physiology and pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Cytoprotective effects of autophagy modulators have thus far only been reported in animal models of kidney disease, and evidence that these findings can be translated to humans is currently lacking.

    “Importantly, the cytoprotective effects of autophagy modulators have thus far only been reported in animal models of kidney disease, and evidence that these findings can be translated to humans is currently lacking.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Targets of candidate autophagy-modulating agents might regulate cellular processes beyond autophagy, and their pharmacological targeting might result in unexpected harmful side effects.

    “First, the targets of these candidate agents might regulate cellular processes beyond autophagy and their pharmacological targeting might therefore result in unexpected harmful side effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Short-term inhibition of mTORC1 with low dose of everolimus in 24-month-old rats dramatically reduces age-related kidney disease and counter-regulates age-related gene expression changes in kidney.

    “Another study demonstrated that short-term inhibition of mTORC1 with a low dose of everolimus in 24-month-old rats dramatically reduced age-related kidney disease and even counter-regulated age-related gene expression changes in the kidney185.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Shavlakadze, T. et al. Short-term low-dose mTORC1 inhibition in aged rats counter-regulates age-related gene changes and blocks age-related kidney pathology. J. Gerontol. A Biol. Sci. Med. Sci. 73, 845–852 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mTOR inhibitors such as rapamycin, rapamycin analogues and mTORC1 kinase inhibitors are widely used as immunosuppressive agents in clinical settings.

    “mTOR inhibitors, such as rapamycin, rapamycin analogues and mTORC1 kinase inhibitors, are already widely used as immunosuppressive agents in clinical settings18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Timing, duration and magnitude of autophagy modulation should be carefully considered to maximize protective effect.

    “Therefore, the timing, duration and magnitude of autophagy modulation should be carefully considered to maximize its protective effect.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Precise function of autophagy in kidney fibrosis remains controversial.

    “Notably, the precise function of autophagy in kidney fibrosis remains controversial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Contribution of autophagy to anti-ageing effects of everolimus was not investigated in this study.

    “However, the contribution of autophagy to the anti-ageing effects of everolimus was not investigated in this study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Autophagy activation in PTECs during AKI is renoprotective, whereas autophagy induction in leukocytes might improve cell survival and promote inflammation.

    “For example, autophagy activation in PTECs during AKI is renoprotective, whereas autophagy induction in leukocytes might improve cell survival and promote inflammation200.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Larson-Casey, J. L., Deshane, J. S., Ryan, A. J., Thannickal, V. J. & Carter, A. B. Macrophage Akt1 kinase-mediated mitophagy modulates apoptosis resistance and pulmonary fibrosis. Immunity 44, 582–596 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Side effects of long-term or complete mTORC1 inhibition in kidney cells are well-recognized, such as early onset of proteinuria caused by specific inhibition of mTORC1 activity in podocytes in mice and disruption of kidney tubular homeostasis caused by specific inhibition of mTORC1 activity in kidney tubular cells in mice.

    “However, the side effects of long-term or complete mTORC1 inhibition in kidney cells have been well-recognized, such as the early onset of proteinuria caused by specific inhibition of mTORC1 activity in podocytes in mice and the disruption of kidney tubular homeostasis caused by specific inhibition of mTORC1 activity in kidney tubular cells in mice51,80.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011). source

      Not checked in the free run.

    • cites [80] Grahammer, F. et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc. Natl Acad. Sci. USA 111, E2817–E2826 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In aged mice, long-term calorie restriction restores autophagic activity through activation of SIRT1-FOXO3 axis, which attenuates mitochondrial oxidative damage and protects against hypoxia-induced oxidative stress and mitochondrial damage in ageing kidneys.

    “In aged mice, long-term calorie restriction restored autophagic activity through the activation of the SIRT1–FOXO3 axis, which attenuated mitochondrial oxidative damage and protected against hypoxia-induced oxidative stress and mitochondrial damage in ageing kidneys79.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Lempiainen, J. et al. Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1alpha-eNOS pathway and enhanced autophagy. Acta Physiol. 208, 410–421 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calorie restriction enhances autophagy and mitigates most age-related damage in podocytes and convoluted proximal tubules.

    “Another study demonstrated that calorie restriction enhanced autophagy and mitigated most of the age-related damage in podocytes and convoluted proximal tubules184.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Calvo-Rubio, M. et al. Dietary fat composition influences glomerular and proximal convoluted tubule cell structure and autophagic processes in kidneys from calorie-restricted mice. Aging Cell 15, 477–487 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PKD is one of the most common ciliopathies and these disorders are associated with decreased autophagy.

    “PKD is one of the most common ciliopathies and these disorders are associated with decreased autophagy174.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B. & Christensen, S. T. Cellular signalling by primary cilia in development, organ function and disease. Nat. Rev. Nephrol. 15, 199–219 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    mTOR has opposite effects on autophagy and cell growth and differentiation; mTOR inhibitors might provide renoprotection by activating autophagy but might also inhibit cell growth and hinder kidney repair.

    “For example, mTOR has opposite effects on autophagy and cell growth and differentiation — mTOR inhibitors might provide renoprotection by activating autophagy, but they might also inhibit cell growth and therefore hinder kidney repair198,199.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [198] Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016). source

      Not checked in the free run.

    • cites [199] Viana, S. D., Reis, F. & Alves, R. Therapeutic use of mTOR inhibitors in renal diseases: advances, drawbacks, and challenges. Oxid. Med. Cell Longev. 2018, 3693625 (2018). source

      Not checked in the free run.

163 of 163

  • The paper relies on this without support.

    Findings from rodent models of kidney injury and disease are informative about human kidney physiology and disease.

    “rodent models of AKI induced by kidney ischaemia–reperfusion injury (IRI), by nephrotoxic drugs such cisplatin, by sepsis and other AKI risk factors”

  • The paper relies on this without support.

    Autophagy reporter signals such as LC3 puncta and mito-QC mitolysosomes reflect autophagic flux or activity.

    “Mito-QC mice express a tandem mCherry–GFP protein fused to the outer mitochondrial membrane mitochondrial fission 1 protein (encoded by FIS1); the differential pH sensitivities between mCherry and GFP enable tracking of the delivery of mitochondria to lysosomes to form mitolysosomes”

  • The paper relies on this without support.

    Genetic deletion of autophagy genes in mouse kidney cells models human autophagy deficiency in kidney disease.

    “selective deletion of Atg5 or Atg7 in proximal tubules resulted in progressive kidney damage and premature kidney ageing”

  • The paper relies on this without support.

    Pharmacological modulation of autophagy in animal models will translate into therapeutic benefit for human kidney diseases.

    “promoting autophagy through pharmacological inhibition of mTORC1, or activation of AMPK or sirtuins, has been shown to be renoprotective during AKI”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Phenotypic alterations associated with suppression of autophagy within multiple components of the renal system become clinically manifest or exhibit worsened features with age.

    “Of note, the phenotypic alterations associated with the suppression of autophagy within multiple components of the renal system become clinically manifest (or exhibit worsened features) with age, implying that defective autophagy is a primary driver of kidney aging (Tang et al, 2020).”

    From Autophagy in major human diseases (2021) · cites this paper as Tang et al, 2020

  • Defective autophagy is a primary driver of kidney aging.

    “Of note, the phenotypic alterations associated with the suppression of autophagy within multiple components of the renal system become clinically manifest (or exhibit worsened features) with age, implying that defective autophagy is a primary driver of kidney aging (Tang et al, 2020).”

    From Autophagy in major human diseases (2021) · cites this paper as Tang et al, 2020

  • Intact autophagic responses are essential to regulate baseline functions of resident kidney cells and exert renoprotective effects under acute or chronic damage.

    “Intact autophagic responses are essential to regulate baseline functions of resident kidney cells, while exerting renoprotective effects under conditions of acute or chronic damage (Choi, 2020; Tang et al, 2020) (Table 5).”

    From Autophagy in major human diseases (2021) · cites this paper as Tang et al, 2020

  • Inactivation of autophagy in TECs exacerbates the noxious effects of IRI, sensitizing kidney-resident cells to death.

    “Regardless of the experimental setting, inactivation of autophagy in TECs exacerbates the noxious effects of IRI, sensitizing kidney‐resident cells to death (Kaushal & Shah, 2016; Choi, 2020; Tang et al, 2020).”

    From Autophagy in major human diseases (2021) · cites this paper as Tang et al, 2020

The citation lists haven’t been fetched yet

References 205 · Cited by 496

Authors
Tang, C., Livingston, M. J., Liu, Z., & Dong, Z.
Affiliations
  • Central South University (CN)
  • Augusta University (US)
Corresponding author
Dong, Zheng
ORCID
Venue
Nature Reviews Nephrology
Publisher
Springer Science and Business Media LLC
Published
2020-07-23
Volume
16
Issue
9
Pages
489-508
ISSN
  • 1745-8323 (ISSN-L)
  • 1759-5061
  • 1759-507X
DOI
10.1038/s41581-020-0309-2
PMC
PMC7868042
OpenAlex
W3044253363
Cited by
496
References
205
Citations by year
2026: 69 · 2025: 97 · 2024: 95 · 2023: 95 · 2022: 92 · 2021: 45 · 2020: 3
FWCI
8.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Nephrology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000319, IK6 BX005236)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK087843, R01DK058831)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
autophagy, kidney homeostasis, kidney disease, acute kidney injury, chronic kidney disease, diabetic nephropathy, focal segmental glomerulosclerosis, polycystic kidney disease, kidney aging, renal fibrosis, mTOR, AMPK, sirtuins, autophagic flux, glomerular disease, tubulointerstitial disease, kidney repair
MeSH terms
Aging, Autophagy, Diabetic Nephropathies, Fibrosis, Glomerulosclerosis, Focal Segmental, Homeostasis, Humans, Kidney Glomerulus, Kidney Tubules, Proximal, Polycystic Kidney Diseases, Signal Transduction, Sirtuins, Renal Insufficiency, Chronic, AMP-Activated Protein Kinases, Acute Kidney Injury, TOR Serine-Threonine Kinases, Mitophagy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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