Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney.
BACKGROUND
Somatic cells in vitro have a finite life expectancy before entering a state of senescence. If this state has an in vivo counterpart, it could contribute to organ aging. We have previously shown that human kidney cortex displays telomere shortening with age. In the present study, we evaluated the relationship between renal age in humans and a number of phenomena associated with cellular senescence in vitro.


METHODS
Human kidney specimens were obtained at 8 weeks to 88 years of age and were assessed for changes related to aging.


RESULTS
We found that human kidneys expressed relatively constant levels of mRNAs for genes potentially related to senescence. Among the candidate genes surveyed, the cell cycle regulator p16INK4a emerged with the strongest association with renal aging for both mRNA and protein expression. Proliferation as measured by Ki-67 expression was inversely correlated with p16INK4a expression, compatible with a role for p16INK4a as an irreversible cell cycle inhibitor. Cyclooxygenase 1 and 2 (COX-1 and COX-2) mRNA expression was elevated in older kidneys, associated with increased protein expression. Comparison of gene expression with age-related histologic changes revealed that glomerulosclerosis correlated with p16INK4a and p53, whereas interstitial fibrosis and tubular atrophy were associated with p16INK4a, p53, COX-1, transforming growth factor-beta 1 (TGF-beta 1), and heat shock protein A5 (HSPA5).


CONCLUSIONS
We conclude that some changes observed in cellular senescence in vitro do occur in human kidney with age, particularly in the renal cortex, in some cases correlating with histologic features. P16INK4a emerged with the most consistent correlations with age and histologic changes and inversely correlated with cell replication.
Melk
Anette
A
Division of Nephrology and Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. annettemelk@yahoo.de
Schmidt
Bernhard M W
BM
Takeuchi
Oki
O
Sawitzki
Birgit
B
Rayner
David C
DC
Halloran
Philip F
PF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000235:genetics; D019394:Ki-67 Antigen / Q000235:genetics; D007668:Kidney / Q000502:physiology*; D007674:Kidney Diseases / Q000503:physiopathology*; D008062:Lipofuscin / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
D019941:Cyclin-Dependent Kinase Inhibitor p16; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D007527:Isoenzymes; D019394:Ki-67 Antigen; D008062:Lipofuscin; D008565:Membrane Proteins; D012333:RNA, Messenger; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases