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Am J Physiol Renal Physiol. 2018 Dec 1;315(6):F1833-F1842. doi: 10.1152/ajprenal.00608.2017. Epub 2018 Sep 12.

Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

Author information

1
Institute of Translational Research, Ochsner Health System , New Orleans, Louisiana.
2
Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
3
Immunology and Inflammation Center, Feinstein Institute for Medical Research and Zucker School of Medicine at Hofstra-Northwell, Manhasset, New York, New York.
4
Department of Microbiology, Tulane Primate Center, Tulane University , New Orleans, Louisiana.
5
Department of Experimental Oncology, European Institute of Oncology , Milan , Italy.
6
Department of Pathology and Laboratory of Medicine, University of North Carolina , Chapel Hill, North Carolina.
7
Department of Stem Cell and Regenerative Medicine, Tulane University , New Orleans, Louisiana.

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 the 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 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium 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 medium. 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 the 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.

KEYWORDS:

aging; diabetes

PMID:
30207172
PMCID:
PMC6336986
DOI:
10.1152/ajprenal.00608.2017

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