A neutralizing VEGF antibody prevents glomerular hypertrophy in a model of obese type 2 diabetes, the Zucker diabetic fatty rat

Abstract

Antagonism of vascular endothelial growth factor (VEGF) has improved the outcome in experimental nephropathies of various origins, including diabetic nephropathy in a type 1 diabetic rat model and a type 2 diabetic mouse model. Neutralizing VEGF antibodies prevented glomerular hypertrophy in these models. We examined the renal effects of VEGF blockade in an obese rat model of type 2 diabetic nephropathy and investigated the mechanism underlying the inhibition of glomerular hypertrophy. Twenty female Zucker diabetic fatty (ZDF) rats, fed a high-fat diet and aged 10 weeks, were treated with VEGF antibodies or an irrelevant isotype-matched IgG. Ten heterozygous (fa/+) littermates served as additional non-diabetic, lean controls. Urinary albumin excretion (UAE) and creatinine clearance (CrCl) were assessed at baseline, and at 3 and 5 weeks. Kidney weight and glomerular volume were determined at the end of the study. Glomerular apoptosis was examined with anti-active caspase-3 immunohistochemistry. All obese animals had established diabetes, hyperlipidaemia and normal blood pressure, which were not influenced by VEGF antibody treatment. ZDF control rats had increased UAE, CrCl, kidney weights and glomerular volumes compared with non-diabetic, lean control rats. VEGF antibody treatment prevented the glomerular hypertrophy, but did not affect UAE, CrCl and kidney weight. Glomerular anti-active caspase-3 immunostaining was not different between the groups. Inhibition of VEGF prevented early glomerular hypertrophy in ZDF rats with established diabetes. Increased apoptosis of glomerular endothelial cells does not appear to underly the inhibition of glomerular growth.