PMID- 25760322
OWN - NLM
STAT- MEDLINE
DCOM- 20160520
LR  - 20220408
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 88
IP  - 1
DP  - 2015 Jul
TI  - Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion 
      injury by impairing autophagy.
PG  - 85-94
LID - 10.1038/ki.2015.69 [doi]
AB  - 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.
FAU - Cheng, Huifang
AU  - Cheng H
AD  - 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.
FAU - Fan, Xiaofeng
AU  - Fan X
AD  - Division of Nephrology, Department of Medicine, C3121 MCN, Vanderbilt University 
      School of Medicine, Nashville, Tennessee, USA.
FAU - Lawson, William E
AU  - Lawson WE
AD  - 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.
FAU - Paueksakon, Paisit
AU  - Paueksakon P
AD  - Department of Pathology, Microbiology and Immunology, Vanderbilt University 
      School of Medicine, Nashville, Tennessee, USA.
FAU - Harris, Raymond C
AU  - Harris RC
AD  - 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.
LA  - eng
GR  - DK51265/DK/NIDDK NIH HHS/United States
GR  - I01 BX000320/BX/BLRD VA/United States
GR  - DK95785/DK/NIDDK NIH HHS/United States
GR  - R01 DK095785/DK/NIDDK NIH HHS/United States
GR  - R01 DK051265/DK/NIDDK NIH HHS/United States
GR  - DK62794/DK/NIDDK NIH HHS/United States
GR  - R01 DK062794/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150311
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (telomerase RNA)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.7.49 (Telomerase)
RN  - EC 2.7.7.49 (Tert protein, mouse)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Acute Kidney Injury/*enzymology/etiology/pathology
MH  - Aging/physiology
MH  - Animals
MH  - Apoptosis
MH  - *Autophagy
MH  - Blood Urea Nitrogen
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - Disease Models, Animal
MH  - Epithelial Cells/drug effects/metabolism
MH  - Kidney/*physiology
MH  - Kidney Tubules, Proximal/cytology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - RNA/genetics
MH  - Regeneration/*physiology
MH  - Reperfusion Injury/complications
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Telomerase/*deficiency/genetics
MH  - Telomere Shortening
PMC - PMC4490111
MID - NIHMS662278
EDAT- 2015/03/12 06:00
MHDA- 2016/05/21 06:00
PMCR- 2016/01/01
CRDT- 2015/03/12 06:00
PHST- 2014/07/08 00:00 [received]
PHST- 2015/01/19 00:00 [revised]
PHST- 2015/01/22 00:00 [accepted]
PHST- 2015/03/12 06:00 [entrez]
PHST- 2015/03/12 06:00 [pubmed]
PHST- 2016/05/21 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - S2157-1716(15)32149-3 [pii]
AID - 10.1038/ki.2015.69 [doi]
PST - ppublish
SO  - Kidney Int. 2015 Jul;88(1):85-94. doi: 10.1038/ki.2015.69. Epub 2015 Mar 11.