Overexpression of renin in the liver impairs glucose tolerance

Abstract

Animal and clinical studies have pointed to a potential role of the Renin Angiotensin System (RAS) in diabetes. However, mechanisms underlying this association are not completely understood. The objective of this work is to dissect the mechanisms by which overexpression of RAS mediates glucose intolerance, using a transgenic mouse model overexpressing renin in the liver (RenTg; Caron et al., 2002), resulting in constitutively elevated plasma angiotensin II (Ang II). Twenty week-old RenTg mice exhibit significantly impaired glucose tolerance and fasting insulinemia, despite normal glycemia, leptinemia and adiponectinemia, as compared to their wild type littermates. Although adipokine gene expression did not differ across genotypes, the type 2 Ang II receptor was markedly down-regulated in adipose tissue of RenTg mice. Comparative proteomics of adipose tissue from these mice indicates a genotype-dependent differential expression of several proteins associated with diabetes and glucose metabolism. We are currently studying these candidate proteins to identify their role in RAS-induced diabetes. These studies demonstrate that overexpression of renin impairs glucose tolerance and further support the role of RAS in the pathogenesis of diabetes. Future studies will dissect mechanism(s) and tissue(s) linking RAS to diabetes. This work was supported by the TN agricultural experiment station and by the Office of Science, U.S. Dept. of Energy.