Podocyte-directed VEGFC gene therapy prevents increased glomerular permeability and glycocalyx damage in experimental type 1 diabetes

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, and current interventions fail to directly target the glomerulus, where the disease initiates. Vascular endothelial growth factor (VEGF)C is a key contributor to glomerular endothelial barrier function. In transgenic mice, podocyte-specific overexpression of human VEGFC was protective in early DKD. Here, we investigated the therapeutic potential of a podocyte-targeted VEGFC gene therapy in DKD. We employed an adeno-associated virus (AAV2/9) to drive human VEGFC in human and mouse podocytes. Expressed VEGFC was functional in vitro. In type 1 diabetic mice (induced by streptozotocin), systemic administration of AAV2/9 increased glomerular human VEGFC expression, ameliorating both albuminuria and increased glomerular permeability. Importantly, VEGFC gene therapy also protected the glomerular endothelial glycocalyx, the first barrier to protein in the glomerular filtration barrier. These findings demonstrate that podocyte-directed VEGFC gene delivery can restore glomerular function and protect against early DKD progression. This novel approach represents a promising therapeutic strategy, particularly for patients with type 1 diabetes at risk of DKD, where there is an unmet clinical need.

Keywords: VEGFC; albuminuria; diabetic kidney disease; gene therapy; glomerulus; glycocalyx; type 1 diabetes.