Ezrin Is Down-Regulated in Diabetic Kidney Glomeruli and Regulates Actin Reorganization and Glucose Uptake via GLUT1 in Cultured Podocytes

Diabetic nephropathyis a complication of diabetes and a major cause of end-stage renal disease. To characterize the early pathophysiological mechanisms leading to glomerular podocyteinjury in diabetic nephropathy, we performed quantitative proteomicprofiling of glomeruli isolated from rats with streptozotocin-induced diabetes and controls. Fluorescence-based two-dimensional difference gel electrophoresis, coupled with mass spectrometry, identified 29 differentially expressed spots, including actin-binding protein ezrinand its interaction partner, NHERF2, which were down-regulated in the streptozotocingroup. Knockdown of ezrinby siRNA in cultured podocytesincreased glucose uptake compared with control siRNA-transfected cells, apparently by increasing translocation of glucose transporter GLUT1to the plasma membrane. Knockdown of ezrinalso induced actin remodelingunder basal conditions, but reduced insulin-stimulated actinreorganization. Ezrin-dependent actin remodelinginvolved cofilin-1 that is essential for the turnover and reorganization of actinfilaments. Phosphorylated, inactive cofilin-1 was up-regulated in diabetic glomeruli, suggesting altered actindynamics. Furthermore, IHC analysis revealed reduced expression of ezrinin the podocytesof patients with diabetes. Our findings suggest that ezrinmay play a role in the development of the renal complication in diabetes by regulating transport of glucose and organization of the actincytoskeleton in podocytes.