A Major Role of VEGFR1 Blockade in Protecting Glomerular Endothelium in Experimental Diabetes

ABSTRACT Background Microvascular injury is a critical factor in the pathogenesis of diabetic nephropathy. Dysregulation in vascular endothelial growth factor‐A (VEGF‐A) signalling pathways exacerbates endothelial dysfunction, contributing to the progression of kidney disease. In this study, we tested whether selective blockade of VEGFR1, a decoy receptor that limits VEGF‐A availability for VEGFR2, could restore glomerular microvascular integrity in experimental diabetic nephropathy. Methods Male BTBR ob/ob mice, a model of advanced Type 2 diabetic nephropathy, received chronic treatment with a monoclonal antibody blocking VEGFR1. Renal functional parameters, albuminuria and glomerular injury were evaluated and compared with mice treated with the ACE inhibitor lisinopril, used as standard therapy. Glomerular capillary density and filtration barrier integrity were assessed by immunofluorescence and ultrastructural analyses, including evaluation of endothelial fenestrations and glycocalyx preservation. Results VEGFR1 blockade reduced glomerular hyperfiltration, albuminuria and glomerular injury. Unlike lisinopril, VEGFR1 inhibition prevented glomerular capillary rarefaction and preserved the integrity of glomerular filtration barrier components. Ultrastructural analyses demonstrated the maintenance of endothelial fenestrations and glycocalyx coverage, closely resembling that of wild‐type non‐diabetic mice. VEGFR1‐blocking antibody treatment increased circulating VEGF‐A and placental growth factor as well as renal VEGFR2 expression. These vascular outcomes translated into better animal survival, with no mortality among VEGFR1‐blocking antibody‐treated mice. Conclusions Selective VEGFR1 inhibition preserves the structure and function of the glomerular filtration barrier by targeting endothelial injury and ameliorates microvascular integrity. These findings identify VEGFR1 as a critical regulator of diabetic glomerular microvascular damage and suggest modulation of VEGF signalling as a potential therapeutic approach for diabetic nephropathy, for which current therapies provide imperfect renoprotection.