Session: S50-Molecular Basis of Diabetes Complications
Room 303 (Moscone Center)
Hyperglycemia is a major risk factor for the pathogenesis of diabetic nephropathy. Protein kinase-C (PKC) activation induced by hyperglycemia has been shown to cause glomerular abnormalities in rodents similar to those observed in diabetic glomerulopathy. PKC activation has been shown to regulate many cytokines, including vascular endothelial growth factors (VEGF) and TGFβ, both of which have been implicated in diabetic nephropathy. Recent studies have also shown that VEGF deficiency will also cause severe glomerular pathologies suggesting that loss of VEGF action may also be important in the pathogenesis of nephropathy. However, VEGF expression in the renal glomeruli is increased in diabetes, which makes it uncertain whether the elevation of VEGF has a detrimental or protective role in renal glomeruli with the presence of diabetes. Our studies show that diabetes can cause PKC activation, especially the delta and beta isoforms in glomerular cells which can inhibit VEGF production and actions enhance angiotensin activation and inhibit the protective actions of GLP-1. We suggest that the loss of protective functions of VEGF, GLP-1 and insulin with the augmentation of angiotensin leads to endothelial and protocyte dysfunction in glomeruli and are major contributors to diabetic nephropathy.