Amelioration of Long-Term Renal Changes in Obese Type 2 Diabetic Mice by a Neutralizing Vascular Endothelial Growth Factor Antibody

Abstract

Diabetic nephropathy in type 2 diabetic patients is a frequent complication associated with increased morbidity and mortality. Various growth factors and cytokines have been implicated in the pathogenesis of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To explore a role for VEGF in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine VEGF antibody in the diabetic db/db mouse, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with a VEGF antibody, while another db/db group was treated for the same period with an isotype-matched irrelevant IgG. A third group consisting of nondiabetic db/+ mice was treated with the same isotype-matched IgG for 2 months. Placebo-treated db/db mice showed a pronounced increase in kidney weight, glomerular volume, basement membrane thickness (BMT), total mesangial volume, urinary albumin excretion (UAE), and creatinine clearance (CrCl) when compared with nondiabetic controls. In VEGF antibody-treated db/db mice, increases in kidney weight, glomerular volume, BMT, and UAE were attenuated, whereas the increase in CrCl was abolished. VEGF antibody administration tended to reduce expansion in total mesangial volume. These effects in diabetic animals were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, chronic inhibition of VEGF in db/db mice ameliorates the diabetic renal changes seen in type 2 diabetes.