Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes

Vascular endothelial growth factor (VEGF) is a cytokine that potently stimu lates angiogenesis, microvascular hyperpermeability, and endothelium-depend ent vasodilation, effects that are largely mediated by endothelial nitric o xide synthase (eNOS). The expression of VEGF is pronounced in glomerular vi sceral epithelial cells, but its function in renal physiology and pathophys iology is unknown. VEGF expression is upregulated by high ambient glucose c oncentrations in several cell types in vitro and in glomeruli of diabetic r ats. To assess the role of VEGF in the pathophysiology of early renal dysfu nction in diabetes, monoclonal anti-VEGF antibodies (Ab) were administered to control and streptozotocin-induced diabetic rats for 6 wk after inductio n of diabetes. Based on in vitro binding studies, an adequate serum VEGF in hibitory activity was achieved during the entire course of anti-VEGF Ab adm inistration. Anti-VEGF Ab treatment but not administration of isotype-match ed control Ab decreased hyperfiltration, albuminuria, and glomerular hypert rophy in diabetic rats. VEGF blockade also prevented the upregulation of eN OS expression in glomerular capillary endothelial cells of diabetic rats. A ntagonism of VEGF had no effect on GFR and glomerular volume in control rat s. These results identify VEGF as a pathogenetic link between hyperglycemia and early renal dysfunction in diabetes. Targeting VEGF may prove useful a s a therapeutic strategy for the treatment of early diabetic nephropathy.