Telomere shortening reduces regenerative capacity after acute kidney injury.
Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and first-generation telomerase-deficient mice. Critically short telomeres, increased expression of the cell-cycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourth-generation telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury.
Westhoff
Jens H
JH
Children's Hospital, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Schildhorn
Carolin
C
Jacobi
Christoph
C
Hömme
Meike
M
Hartner
Andrea
A
Braun
Heidi
H
Kryzer
Christine
C
Wang
Chunfang
C
von Zglinicki
Thomas
T
Kränzlin
Bettina
B
Gretz
Norbert
N
Melk
Anette
A
D058186:Acute Kidney Injury / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D007668:Kidney / Q000473:pathology / Q000502:physiology* / Q000601:surgery; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C422952:telomerase RNA; D055513:Connective Tissue Growth Factor; D012313:RNA; D019098:Telomerase