title: Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.
abstract: 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.
authors.affiliation: 1] Department of Medicine, Nashville Veterans Affairs Hospital, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [2] Division of Nephrology, Department of Medicine, C3121 MCN, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Huifang
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Division of Nephrology, Department of Medicine, C3121 MCN, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Fan
authors.affiliation: 1] Department of Medicine, Nashville Veterans Affairs Hospital, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [2] Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Paisit
authors.initials: P
authors.lastname: Paueksakon
authors.affiliation: 1] Department of Medicine, Nashville Veterans Affairs Hospital, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [2] Division of Nephrology, Department of Medicine, C3121 MCN, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001806:Blood Urea Nitrogen; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000502:physiology*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics; D012038:Regeneration / Q000502:physiology*; D015427:Reperfusion Injury / Q000150:complications; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D059506:Telomere Shortening
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C422952:telomerase RNA; D012313:RNA; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase; C509187:Tert protein, mouse; D020123:Sirolimus