Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes

It has been suggested that the cytokine vascular endothelial growth factor (VEGF) has an important role in the pathogenesis of diabetic retinopathy, b ut its role in nephropathy has not been clearly demonstrated. Assessment of VEGF, I-125-VEGF binding, and vascular endothelial growth factor receptor- 2 (VEGFR-2) in the kidney was performed after 3 and 32 weeks of streptozoto cin-induced diabetes. Gene expression of both VEGF and VEGFR-2 was assessed by Northern blot analysis and the localization of the ligand and receptor was examined by in situ hybridization. VEGF and VEGFR-2 protein were also e valuated by immunohistochemistry. Binding of the radioligand I-125-VEGF was evaluated by in vitro and in vivo autoradiography. Diabetes was associated with increased renal VEGF gene expression. VEGF mRNA and protein were loca lized to the visceral epithelial cells of the glomerulus and to distal tubu les and collecting ducts in both diabetic and nondiabetic rats. Renal VEGFR -2 mRNA was increased after 3 weeks of diabetes but not in long-term diabet es. In situ hybridization and immunohistochemical studies revealed that glo merular endothelial cells were the major site of VEGFR-2 expression. In add ition, VEGFR-2 gene expression was detected in cortical and renomedullary i nterstitial cells and on endothelial cells of peritubular capillaries. Ther e was an increase in I-125-VEGF binding sites after 3 but not 32 weeks of d iabetes. The major VEGF binding sites were in the glomeruli. I-125-VEGF bin ding was also observed in medullary rays and in the renal papillae. These s tudies indicate an early and persistent increase in renal VEGF gene express ion in association with experimental diabetes. In addition, an early and tr ansient increase in renal VEGF receptors was also observed in diabetic rats . These findings are consistent with a role for VEGF in mediating some of t he changes observed in the diabetic kidney.