Intra‐renal Administration of VEGF: A Potential Therapeutic Approach for Renovascular Disease

Abstract

Vascular endothelial growth factor (VEGF) promotes microvascular (MV) proliferation and repair. We have shown that a pre-emptive intra-renal administration of VEGF preserves the function of the stenotic kidney by protecting the renal microcirculation. This study was designed to extend those observations and determine whether intra-renal administration of VEGF can halt the progression and reverse renal injury. Unilateral renal artery stenosis (RAS) was induced in 6 pigs and after 6 weeks of RAS, VEGF-165 was single-infused intra-renally (RAS+VEGF, 0.05 ug/kg) in the stenotic kidney and observed for 4 additional weeks. Additional animals were used as normal and untreated RAS time-controls (n=6 each), and followed for 10 weeks. Single-kidney function was assessed in vivo using ultra-fast CT before (6 weeks) and after VEGF (10 weeks). Pigs were then euthanized, the stenotic kidney removed, and the renal microcirculation quantified using 3D micro-CT. Degree of RAS and hypertension were similar in RAS and RAS+VEGF at 6 and 10 weeks. Renal blood flow (RBF), glomerular filtration rate (GFR), and MV density were similarly decreased in all RAS pigs at 6 weeks compared to normal controls. At 10 weeks, RBF, GFR, and MV density remained unchanged in untreated RAS. However, intra-renal VEGF led to a 20–50% increase in RBF, GFR, and perfusion (p<0.05 vs. pre-VEGF) and augmented cortical MV density (p=NS vs. Normal, p<0.05 vs. RAS). A single intra-renal infusion of VEGF into the stenotic kidney reversed renal dysfunction, which was associated and likely mediated by a targeted effect on the renal microvasculature. This study underscores that the renal MV damage and loss is an important determinant of the progression of renal injury and supports the potential of a novel therapeutic approach to protect the kidney in chronic RAS.