Activation of renal signaling pathways in db/db mice with type 2 diabetes

Background. Altered regulation of signaling pathways may contribute to the pathogenesis of renal disease. We examined renal cortical signaling pathway s in type 2 diabetes. Methods. The status of renal cortical signaling pathways was examined in co ntrol and db/db mice with type 2 diabetes in the early phase of diabetic ne phropathy associated with renal matrix expansion and albuminuria. Results. Tyrosine phosphorylation of renal cortical proteins was increased in diabetic mice. Renal cortical activities of phosphatidylinositol 3-kinas e (PI 3-kinase) in antiphosphotyrosine immunoprecipitates. Akt (PKB), and E RK1/2-type mitogen-activated protein (MAP) kinase activities were significa ntly augmented sixfold (P < 0.01), twofold (P < 0.0003), and sevenfold (P < 0.001). respectively, in diabetic mice compared with controls. A part of t he increased renal cortical PI 3-kinase activity was due to insulin recepto r activation. as PI 3-kinase activity associated with beta chain of the ins ulin receptor was increased nearly fourfold(P < 0.0235). Additionally. the kinase activity of the immunoprecipitated insulin receptor P chain was augm ented in the diabetic renal cortex, and tyrosine phosphorylation of the ins ulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunoprecipitates and Akt also were increased threefo ld (P < 0.05) and twofold (P < 0.0002), respectively. However, there was no change in the hepatic insulin receptor-associated PI 3-kinase activity. Ad ditionally, the hepatic ERK1/2-type MAP kinase activity was inhibited by ne arly 50% (P < 0.01). Conclusions. These studies demonstrate that a variety of receptor signaling pathways are activated in the renal cortex of mice with type 2 diabetes, a nd suggest a role for augmented insulin receptor activity in nephropathy of type 2 diabetes.