Telomerase deficiency delays renal recovery in mice after ischemia–reperfusion injury by impairing autophagy
Open accessAbstract
The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each genotype, as assessed by azotemia, proteinuria, acute tubular injury score, and apoptotic tubular epithelial cell index. However, either TerC or TerT knockout significantly delayed recovery compared with wild-type mice. Electron microscopy showed increased autophagosome formation in renal tubular epithelial cells in wild-type mice but a significant delay of their development in TerC and TerT knockout mice. There were also impeded increases in the expression of the autophagosome marker LC3 II, prolonged accumulation of the autophagosome protein P62, an increase of the cell cycle regulator p16, and greater activation of the mammalian target of rapamycin (mTOR) pathway. The mTORC1 inhibitor, rapamycin, partially restored the ischemia/reperfusion-induced autophagy response, without a significant effect on either p16 induction or tubule epithelial cell proliferation. Thus, muting the maintenance of normal telomere length in mice impaired recovery from AKI, owing to an increase in tubule cell senescence and impairment of mTOR-mediated autophagy.
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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”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [99]
After ischaemic acute kidney injury, timely and tightly regulated autophagy is crucial for kidney tubules to survive initial injury, regenerate, and contribute to normal kidney repair.
“These results suggest that, after ischaemic AKI, timely and tightly regulated autophagy is crucial for kidney tubules to survive the initial injury, regenerate and contribute to normal kidney repair”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [99]
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”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [99]
Mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and premature development of age-related pathologies from the second or third generation.
“In particular, mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and a premature development of age-related pathologies from the second or third generation [8, 18–20, 51, 70, 72, 101, 103]”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [20]
Cells with critically short telomeres obtained from the 4th generation of Tert and Terc deficient mice show impaired autophagy, and autophagic flux reduction has been observed in senescent neurons both in vitro and in vivo.
“Additionally, some reports have demonstrated impaired autophagy in cells with critically short telomeres obtained from the 4th generation of Tert and Terc deficient mice [20], and an autophagic flux reduction has been observed in senescent neurons both in vitro and in vivo [80].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [20]
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References 64 · Cited by 89
- Authors
- Cheng, H., Fan, X., Lawson, W. E., Paueksakon, P., & Harris, R. C.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Harris, Raymond C.
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 88
- Issue
- 1
- Pages
- 85-94
- ISSN
- 0085-2538 (ISSN-L)
- PMC
- PMC4490111
- OpenAlex
- W1981770096
- Cited by
- 89
- References
- 64
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 12 · 2021: 9 · 2020: 12 · 2019: 7 · 2018: 11 · 2017: 5 · 2016: 7 · 2015: 3
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000320)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-51265, R01DK051265, DK62794, DK95785, R01DK062794, R01DK095785)
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- telomerase deficiency, telomere shortening, acute kidney injury, ischemia-reperfusion injury, autophagy, renal function recovery, p16, mTOR signaling, rapamycin, LC3-II, p62, aging
- MeSH terms
- Aging, Animals, Autophagy, Blood Urea Nitrogen, Cells, Cultured, Disease Models, Animal, Epithelial Cells, Kidney, Kidney Tubules, Proximal, Male, Mice, Inbred C57BL, Regeneration, RNA, Signal Transduction, Reperfusion Injury, Apoptosis, Mice, Knockout, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Sirolimus, Cell Proliferation, Mice, Acute Kidney Injury, TOR Serine-Threonine Kinases, Telomere Shortening
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