The impact of vascular disease on morbidity and mortality is on the rise in the Western world. Atherosclerotic renal artery stenosis (ARAS), a common etiology of chronic kidney disease and renovascular hypertension, amplifies deterioration of renal function and attenuates its recovery (compared to RAS alone) following renal revascularization. However, the mechanisms leading to these grave outcomes are yet to be identified, and adequate strategies to improve them are in dire need. The working hypothesis underlying this proposal is that atherosclerosis blunts the recovery of the stenotic ARAS kidney by amplifying oxidative stress and microvascular injury that exacerbate renal damage. The corollary of this hypothesis is that antioxidant strategies or replenishment of endothelial cells would restore vascular integrity and improve the function, structure, and recovery prospects of the ARAS kidney. This hypothesis will be tested in a novel pig model of unilateral ARAS that we have developed and characterized, using unique imaging approaches that we have refined to study single-kidney function and structure. We will characterize in vivo single-kidney regional perfusion, GFR, and tubular dynamics, under basal conditions and during challenge, before and after percutaneous transluminal renal angioplasty (PTRA) and stenting. The in vivo studies will be correlated with in vitro studies exploring the in situ 3D architecture of the renal microcirculation, renal redox status, and morphology. These studies will pursue 3 Specific Aims.
Specific Aim 1 will test the hypothesis that the attenuated response of ARAS kidneys to revascularization is driven by amplification of oxidative stress, which modulates renal function and renal tissue remodeling, and will seek predictive factors associated with renal recovery Specific Aim 2 will test the hypothesis that enhanced renal vascular repair, achieved by intra-renal delivery of autologous progenitor cells, would improve renal hemodynamics, function, and structure in ARAS.
Specific Aim 3 will test the hypothesis that enhanced renal vascular repair in ARAS would improve renal outcomes and recovery after PTRA. The proposed studies may greatly advance our understanding of the pathogenesis of renal injury in ARAS, and assist in development of strategies to identify predictors of renal viability and improve the success of treatment. Thus, these studies may contribute towards management of patients with renovascular disease.
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