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

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.

American journal of physiology. Renal physiology. 2018 Sep 12 [Epub ahead of print]

Himanshu Vashistha, L Marrero, Krzysztof Reiss, Ari Cohen, Ashwani Malhotra, Tariq Javed, Allyson E Bradley, Frank Abbruscato, Sixto Giusti, Antonio Jimenez, Smriti Mehra, Deepak Kaushal, Marco Giorgio, Pier Giuseppe Pelicci, Masao Kakoki, Pravin C Singhal, Bruce Bunnell, Leonard G Meggs

Research-Renal Research, Institute of Translational Research, United States., Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center., The University of North Carolina at Chapel Hill., Institute of Translational Research, Ochsner Clinic Foundation., Nephrology, Ochsner Health System, United States., Institute of Translationa Research, Renal Research, Ochsner Clinic Foundation., Nephrology, Ochsner Clinic Foundation., Microbiology, Tulane University., Microbiology, TNPRC, Tulane University., European Institute of Oncology., Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, United States., Medicine, Feinstein Institute for Medical Research, Hofstra Northwell Medical School, United States., Director, Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Science Center, School of Medicine., Nephrolog, Ochsner Clinic Foundation, United States.