C/EBPα deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice
Open accessAbstract
Kidney aging leads to an increased incidence of end-stage renal disease (ESRD) in the elderly, and aging is a complex biological process controlled by signaling pathways and transcription factors. Podocyte senescence plays a central role in injury resulting from kidney aging. Here, we demonstrated the critical role of C/EBPα in podocyte senescence and kidney aging by generating a genetically modified mouse model of chronological aging in which C/EBPα was selectively deleted in podocytes and by overexpressing C/EBPα in cultured podocytes, in which premature senescence was induced by treatment with adriamycin. Moreover, we illuminated the mechanisms by which podocyte senescence causes tubular impairment by stimulating HK-2 cells with bovine serum albumin (BSA) and chloroquine. Our findings suggest that C/EBPα knockout in podocytes aggravates podocyte senescence through the AMPK/mTOR pathway, leading to glomerulosclerosis, and that subsequent albuminuria exacerbates the epithelial-mesenchymal transdifferentiation of senescent tubular cells by suppressing autophagy. These observations highlight the importance of C/EBPα as a new potential target in kidney aging.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Senescent cells are observed in kidneys of mouse models of acute kidney injury, diabetic nephropathy, glomerulonephropathy, chronic kidney disease and chronic ischaemic renal injury.
“Senescent cells are also observed in kidneys of mouse models of acute kidney injury, diabetic nephropathy, glomerulonephropathy, chronic kidney disease and chronic ischaemic renal injury140,144–150.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [144]
The Results (Fig. 4; page unavailable) show senescence markers in the kidneys of aging mice, and the Discussion reports greater podocyte senescence and kidney injury after podocyte-specific C/EBPα deletion. The paper does not show senescent cells in mouse models of acute kidney injury, diabetic nephropathy, chronic kidney disease, or chronic ischaemic renal injury; its model is aging-related kidney injury. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn 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”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [67]
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.”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [67]
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”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [67]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849 · see citing works
Extending Healthy Life Span—From Yeast to Humans
Fontana, L., Partridge, L., & Longo, V. D. (2010) · Science · doi:10.1126/science.1172539 · Cited by 3,023 · see citing works
Kenyon, C. J. (2010) · Nature · doi:10.1038/nature08980 · Cited by 2,739 · see citing works
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · see citing works
A Conditionally Immortalized Human Podocyte Cell Line Demonstrating Nephrin and Podocin Expression
Saleem, M. A., O’Hare, M. J., Reiser, J., Coward, R. J., Inward, C. D., Farren, T., Xing, C. Y., Ni, L., Mathieson, P. W., & Mundel, P. H. (2002) · Journal of the American Society of Nephrology · doi:10.1681/asn.v133630 · Cited by 1,122 · see citing works
Senescence-messaging secretome: SMS-ing cellular stress
Kuilman, T., & Peeper, D. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2560 · Cited by 909 · see citing works
The Critical Role of Metabolic Pathways in Aging
Barzilai, N., Huffman, D. M., Muzumdar, R. H., & Bartke, A. (2012) · Diabetes · doi:10.2337/db11-1300 · Cited by 803 · see citing works
Timchenko, N. A., Wilde, M., Nakanishi, M., Smith, J. R., & Darlington, G. (1996) · Genes & Development · doi:10.1101/gad.10.7.804 · Cited by 382 · see citing works
C/EBPα Arrests Cell Proliferation through Direct Inhibition of Cdk2 and Cdk4
Wang, H., Iakova, P. A., Wilde, M., Welm, A. L., Goode, T., Roesler, W. J., & Timchenko, N. A. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00366-5 · Cited by 354 · see citing works
Stress, cell senescence and organismal ageing
de Magalhães, J. P., & Passos, J. F. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.07.001 · Cited by 316 · see citing works
Glassock, R. J., & Rule, A. D. (2012) · Kidney International · doi:10.1038/ki.2012.65 · Cited by 292 · see citing works
Molecular mechanisms of renal aging
Schmitt, R., & Melk, A. (2017) · Kidney International · doi:10.1016/j.kint.2017.02.036 · Cited by 235 · see citing works
Flatt, T. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00148 · Cited by 229 · see citing works
Glomerular Aging and Focal Global Glomerulosclerosis
Hodgin, J. B., Bitzer, M., Wickman, L. T., Afshinnia, F., Wang, S. Q., O'Connor, C. L., Yang, Y., Meadowbrooke, C. C., Chowdhury, M., Kikuchi, M., et al. (2015) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014080752 · Cited by 215 · see citing works
Aging and the Kidneys: Anatomy, Physiology and Consequences for Defining Chronic Kidney Disease
Glassock, R. J., & Rule, A. D. (2016) · The Nephron journals/Nephron journals · doi:10.1159/000445450 · Cited by 195 · see citing works
Unraveling the Role of Podocyte Turnover in Glomerular Aging and Injury
Wanner, N., Hartleben, B., Herbach, N., Goedel, M., Stickel, N., Zeiser, R., Walz, G., Moeller, M. J., Grahammer, F., & Huber, T. B. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013050452 · Cited by 183 · see citing works
Altered expression of C/EBP family members results in decreased adipogenesis with aging
Karagiannides, I., Tchkonia, T., Dobson, D. E., Steppan, C. M., Cummins, P., Chan, G., Salvatori, K., Hadzopoulou‐Cladaras, M., & Kirkland, J. L. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.6.r1772 · Cited by 182 · see citing works
Wang, G., Iakova, P. A., Wilde, M., Awad, S. S., & Timchenko, N. A. (2004) · Genes & Development · doi:10.1101/gad.1183304 · Cited by 140 · see citing works
Bielak-Zmijewska, A., Wnuk, M., Przybylska, D., Grabowska, W., Lewinska, A., Alster, O., Korwek, Z., Cmoch, A., Myszka, A., Pikula, S., et al. (2014) · Biogerontology · doi:10.1007/s10522-013-9477-9 · Cited by 139 · see citing works
Gene expression profiling of replicative and induced senescence
Purcell, M., Kruger, A., & Tainsky, M. A. (2014) · Cell Cycle · doi:10.4161/15384101.2014.973327 · Cited by 132 · see citing works
Cellular senescence: Its role in tumor suppression and aging
Ohtani, N., Mann, D. J., & Hara, E. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01123.x · Cited by 113 · see citing works
Transmitting senescence to the cell neighbourhood
Hoare, M., & Narita, M. (2013) · Nature Cell Biology · doi:10.1038/ncb2811 · Cited by 108 · see citing works
Antonson, P., & Xanthopoulos, K. G. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2439 · Cited by 102 · see citing works
Mechanisms and biological functions of autophagy in diseased and ageing kidneys
Fougeray, S., & Pallet, N. (2014) · Nature Reviews Nephrology · doi:10.1038/nrneph.2014.201 · Cited by 101 · see citing works
Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3
Del Real, M. M., & Rothenberg, E. V. (2013) · Development · doi:10.1242/dev.088559 · Cited by 95 · see citing works
Podocyte loss involves MDM2 ‐driven mitotic catastrophe
Mulay, S. R., Thomasová, D., Ryu, M., Kulkarni, O. P., Migliorini, A., Bruns, H., Gröbmayr, R., Lazzeri, E., Lasagni, L., Liapis, H., et al. (2013) · The Journal of Pathology · doi:10.1002/path.4193 · Cited by 71 · see citing works
C/EBPα regulates macrophage activation and systemic metabolism
Lee, B., Qiao, L., Lu, M. M., Yoo, H. S., Cheung, W., MAK, R. H. K., Schaack, J. B., Feng, G., Chi, N., Olefsky, J. M., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00002.2014 · Cited by 59 · see citing works
Zhang, L., Liu, J., Zhou, F., et al. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.8433 · Cited by 49 · see citing works
Self-citationModulation of vitamin D signaling by the pioneer factor CEBPA
Nurminen, V., Neme, A., Seuter, S., & Carlberg, C. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2018.12.004 · Cited by 49 · see citing works
Li, G., Li, C., Xia, M., Ritter, J. K., Gehr, T. W. B., Boini, K. M., & Li, P. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373989 · Cited by 48 · see citing works
Zhuo, L., Cai, G., Liu, F., Fu, B., Liu, W., Hong, Q., Ma, Q., Peng, Y., Wang, J., & Chen, X. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.08.005 · Cited by 40 · see citing works
Self-citationYang, H., Hong, H., Luo, W., Dai, C.-M., Chen, X.-Y., Wang, L., Li, Q., Li, Z., Liu, P., & Li, Z.-M. (2018) · Acta Pharmacologica Sinica · doi:10.1038/s41401-018-0079-6 · Cited by 39 · see citing works
Zhou, J., Li, H., Xia, X., Herrera, A., Pollock, N., Reebye, V., Sodergren, M. H., Dorman, S., Littman, B. H., Doogan, D. P., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.018 · Cited by 37 · see citing works
Role of C/EBP-α in Adriamycin-induced podocyte injury
Zhong, F., Wang, W., Lee, K., et al. (2016) · Scientific Reports · doi:10.1038/srep33520 · Cited by 26 · see citing works
Self-citationIntermittent mTOR Inhibition Reverses Kidney Aging in Old Rats
Francesco, A. D., Díaz‐Ruiz, A., de Cabo, R., & Bernier, M. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly023 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cellular senescence: the good, the bad and the unknown
Huang, W., Hickson, L. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00601-z · Cited by 1,150 · see citing works
Autophagy in kidney homeostasis and disease
Tang, C., Livingston, M. J., Liu, Z., & Dong, Z. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-0309-2 · Cited by 496 · see citing works
SenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
- Authors
- Zhang, L., Zhou, F., Yu, X., Zhu, Y., Zhou, Y., Liu, J., Liu, Y., Ma, Q., Zhang, Y., Wang, W., & Chen, N.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Wang, Weiming
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2019-09-17
- Volume
- 10
- Issue
- 10
- Pages
- 684-684
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6746733
- OpenAlex
- W2973433258
- Cited by
- 48
- References
- 35
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 14 · 2023: 11 · 2022: 9 · 2021: 3 · 2020: 2 · 2018: 1
- FWCI
- 2.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Adobe Systems
- National Natural Science Foundation of China (81870492, 81270782, 81900699)
- Science and Technology Commission of Shanghai Municipality (15140902800)
- National Key Research and Development Program of China (81900699, 2012CB517701, 81870492, 81270782, 2016YFC1305402, 15140902800)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- C/EBPα, kidney aging, glomerulosclerosis, albuminuria, AMPK/mTOR signaling, autophagy, epithelial-mesenchymal transition, renal tubular injury, chronic kidney disease, aged mice
- MeSH terms
- Age Factors, Animals, Cell Line, Disease Models, Animal, Humans, Kidney Diseases, Male, Mice, Inbred C57BL, Mice, Transgenic, Cellular Senescence, Mice, Knockout, CCAAT-Enhancer-Binding Protein-alpha, Podocytes, Mice
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
