title: Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney.
abstract: Some features of kidney transplants with dysfunction overlap the lesions of aging, such as tubular atrophy and interstitial fibrosis (TA/IF) without major glomerular abnormalities. Somatic cell limitations could contribute to deterioration in aging and disease states. Since expression of p16(INK4a), a cell cycle inhibitor associated with somatic cell senescence in vitro, is induced in aged kidney, we studied whether kidneys with dysfunction and TA/IF manifested increased p16(INK4a) expression. We performed p16(INK4a) immunostaining on transplanted kidneys and native kidneys with chronic renal diseases. At implantation, transplants manifested little TA/IF, and nuclear p16(INK4a) immunostaining was consistent with age. However, transplants biopsied for abnormal function displaying TA/IF showed strong nuclear and cytoplasmic p16(INK4a) staining, beyond the amount predicted for age. Both atrophic and non-atrophic nephrons displayed increased p16(INK4a), suggesting that it was not simply a feature of atrophy. Epithelial p16(INK4a) staining was not increased in transplants with good function, but was increased in diseased native kidneys. The finding of increased p16(INK4a) expression in renal transplants and diseased kidneys with TA/IF and impaired function supports the concept that some cell senescence changes that accompany aging are also induced by injury and disease stresses. Thus, aging, injury and disease may share common pathways involving somatic cell senescence.
authors.affiliation: Division of Nephrology and Transplantation Immunology, Department of Medicine, University of Alberta, Edmonton, Canada. anette.melk@med.uni-heidlberg.de
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
authors.forename: Bernhard M W
authors.initials: BM
authors.lastname: Schmidt
authors.forename: Attapong
authors.initials: A
authors.lastname: Vongwiwatana
authors.forename: David C
authors.initials: DC
authors.lastname: Rayner
authors.forename: Philip F
authors.initials: PF
authors.lastname: Halloran
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16