Manipulation of VEGF-A splicing using natural compounds as a potential therapeutic in diabetic nephropathy

Abstract

Alternative splicing of vascular endothelial growth factor (VEGF-A) gives rise to isoform families, the pro-angiogenic VEGF-Axxx and the anti-angiogenic VEGF-Axxxb. VEGF-A165b has previously been shown to be protective in several murine models of renal disease, as well as providing cytoprotection to podocytes in culture. This study aimed to investigate whether a blueberry extract that promotes VEGF-A­165b expression, is a potential therapeutic in a mouse model of type I diabetic nephropathy. The natural extract had no effect on blood glucose levels, but did delay the onset/progression of albuminuria in diabetic mice, and prevented increases in glomerular water permeability. Diabetic control mice had a reduced glomerular expression of nephrin and reduced glomerular capillary circumference, which were rescued when treated with the natural extract. HUVECs displayed reduced tube formation when treated with the natural extract, which was rescued upon addition of Ab-VEGF-A165b. Certain unknown compounds within the blueberry extract are able to switch VEGF-A splicing to promote VEGF-A165b expression in podocytes. The extract plays a protective role in the prevention and treatment of diabetic nephropathy in the DBA/2J type I diabetic mouse model. This study highlights the therapeutic potential of switching VEGF-A splicing to promote VEGF-A165b in diabetic nephropathy.