Systemic Administration of a Biopolymer‐delivered VEGF Improved Renal Hemodynamics and Microvascular Rarefaction in Renal Artery Stenosis

Abstract

Elastin-like polypeptides (ELP) are drug delivery vectors that can be fused to therapeutic compounds to increase their efficacy. ELPs have high affinity for kidney tissue. We showed that the stenotic kidney in renal artery stenosis (RAS) develops progressive loss of function and renal microvascular (MV) damage associated to loss of vascular endothelial growth factor (VEGF). We designed a novel ELP-VEGF121 fusion and tested its therapeutic potential for the kidney after systemic (IV) administration. We hypothesized that IV ELP-VEGF therapy will preserve the stenotic kidney function and microcirculation. Unilateral RAS was induced in 10 pigs. After 6 weeks, stenotic kidney blood flow (RBF) and filtration (GFR) was quantified in vivo using multi-detector computed tomography. Then, pigs were randomized in placebo (RAS) or treated with a single IV infusion of ELP-VEGF121 (RAS+ELP-VEGF, 1 mg/kg, n=5 each). Pigs were observed for 4 weeks, in vivo studies repeated and then euthanized for ex vivo studies. Hypertension and degree of stenosis was similar in RVD and RVD+ELP-VEGF treated pigs. Stenotic kidney RBF and GFR were similarly reduced in all RVD animals after 6 weeks, remained attenuated in RVD at 10 weeks but were significantly improved (albeit not normalized) after IV ELP-VEGF, accompanied by ameliorated cortical and medullary vascular rarefaction A single IV administration of an ELP-VEGF121 construct improved stenotic kidney hemodynamics, filtration, and reduced cortical microvascular damage in RAS. Our study supports the therapeutic feasibility of systemic administration of a novel compound never tested before for renoprotection.