Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity

Abstract

Insulin resistance has been associated with the progression of chronic kidney disease in both diabetes and obesity. This study characterizes insulin signaling in renal tubules and glomeruli in insulin resistant and diabetic states. Insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide (eNOS), and glycogen synthase kinase 3α (GSK3α) were selectively inhibited in the glomeruli but not in the renal tubules of both streptozotocin (STZ)-diabetic and Zucker fatty, insulin resistant rats compared to non-diabetic and Zucker lean rats. Protein levels, but not the mRNA expression, of IRS1 were decreased only in the glomeruli of STZ-diabetic rats and increased its association with ubiquitination. Protein kinase C (PKC) β isoform inhibitor, ruboxistaurin (RBX), treatment enhanced insulin actions and elevated IRS1 expression. In glomerular endothelial cells, high glucose inhibited phosphorylation of Akt, eNOS and GSK3α, decreased IRS1 protein expression and increased association with ubiquitination. Overexpression of IRS1 or the addition of RBX reversed the inhibitory effects of high glucose. Selective inhibition of the IRS1/PI3K/Akt pathway and insulin activation of eNOS and GSK3α in the glomeruli in diabetes and insulin resistance is partly due to increased IRS1 degradation and PKCβ activation. The loss of insulin's effect on endothelial eNOS and GSK3α activation may contribute to the glomeropathy observed in diabetes and obesity.

Blood–brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice

“…39 Treatment with the PKCb inhibitor Enzastaurin did not affect body weight in db/db mice when administered daily for two weeks beginning at eight weeks old (db/Enz; 50/mg/kg/d, PO; F 2,27 ¼ 12.87, p < 0.01; Figure 1(a)). Consistent with the reductions in body weight reported following administration of ruboxistaurin, a related PKCb inhibitor, 40 Enzastaurin reduced weight gain in Wt mice (two-week weight gain, grams; mean AE SEM, Wt/Veh ¼ 6.5 AE 1.1, Wt/Enz ¼ 2.2 AE 0.9). Because Enzastaurin reduced body weights beyond inclusion criteria in Wt mice, subsequent experiments did not include this treatment condition.…”

Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes

“…Another study has extended our under- standing of the insulin signaling in the renal endothelial cells. With the use of two rat models of diabetes, experiments showed that diabetes decreases insulin capability to trigger IRS-1/Akt/ eNOS phosphorylation in renal endothelial cells (23).…”

“…Coward and colleagues showed that podocytes are insulin-responsive cells. Insulin induced an acute increase in glucose uptake in cultured podocyte cell lines and in human podocytes ex vivo due to translocation of the glucose transporters GLUT-1 and GLUT-4 to the plasma membrane (6,23). Interestingly, renal disease similar to DN can be observed in patients with a genetic mutation of the insulin receptor (IR) (25).…”

Metabolic syndrome and insulin signaling in kidney

“…King and colleagues have recently clarified that the responses to insulin in rat models of diabetes and obesity -Zucker lean rats and control SD rats -are different between glomeruli and tubules [62]. In the glomeruli insulin-induced phosphorylation of IRS1, Akt, endothelial nitric oxide synthase (eNOS), and glycogen synthase kinase 3α (GSK3α) were all inhibited in glomeruli but not in the tubules.…”