Title
Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.
Publication Date
2018
Journal Title
Am J Physiol Renal Physiol
Abstract
The p66ShcA protein controls cellular responses to oxidative stress, senescence and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes, by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1 positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of Wild Type (WT) and p66 Knock Out (KO) mice. Cells were plated in culture media containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in Wild Type (WT)-MSCs in HG media in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG media. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self renewal and differentiation. To test the in-vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.
Volume Number
315
Issue Number
6
Pages
F1833-F1842
Document Type
Article
Status
Faculty
Facility
School of Medicine
Primary Department
Nephrology
PMID
DOI
10.1152/ajprenal.00608.2017