Biopolymer-delivered vascular endothelial growth factor improves renal outcomes following revascularization.

Renal angioplasty and stenting (PTRAs) resolves renal artery stenosis, but inconsistently improves renal function, possibly due to persistent parenchymal damage. We developed a bioengineered fusion of a drug delivery vector (elastin-like polypeptide, ELP) with vascular endothelial growth factor (VEGF), and showed its therapeutic efficacy. We tested the hypothesis that combined ELP-VEGF therapy with PTRAs improves renal recovery more efficiently than PTRAs alone, by protecting the stenotic renal parenchyma. Unilateral renovascular disease (RVD) was induced by renal artery stenosis in 14 pigs. Six weeks later, stenotic kidney blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo using multidetector CT. Blood and urine were collected during in vivo studies. All pigs underwent PTRAs and then were randomized into single intrarenal ELP-VEGF administration or placebo (n = 7 each) groups. Pigs were observed for four additional weeks, in vivo CT studies were repeated, and then pigs were euthanized for ex vivo studies to quantify renal microvascular (MV) density, angiogenic factor expression, and morphometric analysis. Renal hemodynamics were similarly blunted in all RVD pigs. PTRAs resolved stenosis but modestly improved RBF and GFR. However, combined PTRAs+ ELP-VEGF improved RBF, GFR, regional perfusion, plasma creatinine, asymmetric dimethlyarginine (ADMA), and albuminuria compared with PTRAs alone, accompanied by improved angiogenic signaling, MV density, and renal fibrosis. Greater improvement of renal function via coadjuvant ELP-VEGF therapy may be driven by enhanced MV proliferation and repair, which ameliorates MV rarefaction and fibrogenic activity that PTRAs alone cannot offset. Thus, our study supports a novel strategy to boost renal recovery in RVD after PTRAs.

A translational model of chronic kidney disease in swine.

Animal models of chronic kidney disease (CKD) are critical for understanding its pathophysiology and for therapeutic development. The cardiovascular and renal anatomy and physiology of the pig are virtually identical to humans. This study aimed to develop a novel translational model of CKD that mimics the pathological features of CKD in humans. CKD was induced in seven domestic pigs by bilateral renal artery stenosis and diet-induced dyslipidemia. Animals were observed for a total of 14 wk. Renal hemodynamics and function were quantified in vivo using multi-detector CT after 6, 10, and 14 wk of CKD. Urine and blood were collected at each time-point, and blood pressure was continuously measured (telemetry). After completion of in vivo studies, pigs were euthanized, kidneys were removed, and microvascular (MV) architecture (µCT), markers of renal injury, inflammation, and fibrosis were evaluated ex vivo. Additional pigs were used as controls ( n = 7). Renal blood flow and glomerular filtration were reduced by 50% in CKD, accompanied by hypertension and elevated plasma creatinine, albumin-to-creatinine ratio and increased urinary KIM-1 and NGAL, suggesting renal injury. Furthermore, 14 wk of CKD resulted in cortical and medullary MV remodeling and loss, inflammation, glomerulosclerosis, tubular atrophy, and tubule-interstitial fibrosis compared with controls. The current study characterizes a novel model of CKD that mimics several of the pathological features observed in human CKD, irrespective of the etiology. Current approaches only slow rather than halt CKD progression, and this novel model may offer a suitable platform for the development of new treatments in a translational fashion.

VEGF therapy for the kidney: emerging strategies.

Renovascular disease (RVD), which is prevalent in the elderly, significantly increases cardiovascular risk and can progressively deteriorate renal function. The loss of renal function in patients with RVD is associated with a progressive dysfunction, damage, and loss of renal microvessels, which can be combined with decreased renal bioavailability of vascular endothelial growth factor (VEGF) and a defective vascular repair and proliferation. This association has been the impetus for recent efforts that have focused on developing methods to stop the progression of renal injury by protecting the renal microvasculature. This mini-review focuses on recent studies supporting potential applications of VEGF therapy for the kidney and discusses underlying mechanisms of renoprotection.

Systemic biopolymer-delivered vascular endothelial growth factor promotes therapeutic angiogenesis in experimental renovascular disease.

We recently developed a therapeutic biopolymer composed of an elastin-like polypeptide (ELP) fused to vascular endothelial growth factor (VEGF) and showed long-term renoprotective effects in experimental renovascular disease after a single intra-renal administration. Here, we sought to determine the specificity, safety, efficacy, and mechanisms of renoprotection of ELP-VEGF after systemic therapy in renovascular disease. We tested whether kidney selectivity of the ELP carrier would reduce off-target binding of VEGF in other organs. In vivo bio-distribution after systemic administration of ELP-VEGF in swine was determined in kidneys, liver, spleen, and heart. Stenotic-kidney renal blood flow and glomerular filtration rate were quantified in vivo using multi-detector computed tomography (CT) after six weeks of renovascular disease, then treated with a single intravenous dose of ELP-VEGF or placebo and observed for four weeks. CT studies were then repeated and the pigs euthanized. Ex vivo studies quantified renal microvascular density (micro-CT) and fibrosis. Kidneys, liver, spleen, and heart were excised to quantify the expression of angiogenic mediators and markers of progenitor cells. ELP-VEGF accumulated predominantly in the kidney and stimulated renal blood flow, glomerular filtration rate, improved cortical microvascular density, and renal fibrosis, and was accompanied by enhanced renal expression of VEGF, downstream mediators of VEGF signaling, and markers of progenitor cells compared to placebo. Expression of angiogenic factors in liver, spleen, and heart were not different compared to placebo-control. Thus, ELP efficiently directs VEGF to the kidney after systemic administration and induces long-term renoprotection without off-target effects, supporting the feasibility and safety of renal therapeutic angiogenesis via systemic administration of a novel kidney-specific bioengineered compound.