Vegfa Protects the Glomerular Microvasculature in Diabetes

Abstract

Vascular endothelial growth factor A (VEGFA) expression is increased in glomeruli in the context of diabetes. Here, we tested the hypothesis that this upregulation of VEGFA protects the glomerular microvasculature in diabetes and that therefore inhibition of VEGFA will accelerate nephropathy. To determine the role of glomerular Vegfa in the development and progression of diabetic nephropathy, we used an inducible Cre-loxP gene-targeting system that enabled genetic deletion of Vegfa selectively from glomerular podocytes of wild-type or diabetic mice. Type 1 diabetes was induced in mice using streptozotocin (STZ). We then assessed the extent of glomerular dysfunction by measuring proteinuria, glomerular pathology, and glomerular cell apoptosis. Vegfa expression increased in podocytes in the STZ model of diabetes. After 7 weeks of diabetes, diabetic mice lacking Vegfa in podocytes exhibited significantly greater proteinuria with profound glomerular scarring and increased apoptosis compared with control mice with diabetes or Vegfa deletion without diabetes. Reduced local production of glomerular Vegfa in a mouse model of type 1 diabetes promotes endothelial injury accelerating the progression of glomerular injury. These results suggest that upregulation of VEGFA in diabetic kidneys protects the microvasculature from injury and that reduction of VEGFA in diabetes may be harmful.