Diabetic Nephropathy: Lessons From the Mouse Article

PMID: 23531985 Web of Science: 000420261000019

Cited authors

  • Vashistha, Himanshu; Meggs, Leonard

Abstract

  • Background: A fundamental problem in the identification of new molecular targets for therapeutic intervention in diabetic nephropathy has been the lack of an experimental mouse model that faithfully recapitulates human diabetic nephropathy.; Methods: Our laboratory, in collaboration with Drs Kakoki and Smithies at the University of North Carolina-Chapel Hill, has developed novel strains of Akita diabetic mice in which the p66 longevity gene has been deleted by homologous recombination. We chose to delete p66 because p66 controls mitochondrial metabolism and cellular responses to oxidative stress, aging, and apoptosis. The redox function of p66 is indispensable for the exponential increase in reactive oxygen species (ROS) associated with diabetes.; Results: p66 null Akita mice express a protection phenotype in kidneys that includes marked attenuation of oxidative stress and glomerular/tubular injury and a striking reduction in urine albumin excretion. Furthermore, the p66 null mutation not only confers a survival advantage to podocytes but also prevents foot process effacement and retains the stationary phenotype. Sirtuin 1 (SIRT1) deacetylase and p66 share overlapping biological functions but induce divergent phenotypes, including opposite effects on longevity, ROS metabolism, cell senescence, and apoptosis. Exciting new data from our laboratory show that SIRT1 is upregulated in the kidneys of p66 null Akita mice and decreases acetylation of p53, which destabilizes the p53 protein and prevents the transcription of p53 proapoptosis genes. Conversely, SIRT1 activates the transcription of FOXO3a-dependent stress gene programs that detoxify ROS and promote the survival phenotype.; Conclusion: We will focus future research on translating these experimental findings in the mouse to clinical diabetic nephropathy.

Authors

Publication date

  • 2013

Published in

International Standard Serial Number (ISSN)

  • 1524-5012

Start page

  • 140

End page

  • 146

Volume

  • 13

Issue

  • 1