Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney by inducing pro-inflammatory mechanisms and disrupting tissue remodeling. Oxidative stress is increased in RVD, but its direct contribution to renal injury has not been fully established. The authors hypothesized that chronic
antioxidant intervention in RVD would improve renal function and attenuate tissue injury.
Single-kidney hemodynamics and function at baseline and during vasoactive challenge were quantified using electron-beam computed tomography in pigs after 12 wk of experimental RVD (simulated by concurrent
hypercholesterolemia and
renal artery stenosis, n = 7), RVD daily supplemented with
antioxidant vitamins C (1 g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal tissue was studied ex vivo using Western blot analysis and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly decreased in the stenotic kidney of both RVD groups. RBF and GFR response to
acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P < 0.05 versus RVD). RVD+Vitamins also showed increased renal expression of
endothelial nitric oxide synthase (eNOS) and decreased expression of
NAD(P)H-oxidase,
nitrotyrosine, inducible-NOS, and
NF-kappaB, suggesting decreased
superoxide abundance and
inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVD+Vitamins was accompanied by augmented expression of extracellular (matrix metalloproteinase-2) and intracellular (
ubiquitin) protein degradation systems, resulting in significantly attenuated glomerulosclerosis and renal
fibrosis. In conclusion, chronic
antioxidant intervention in early experimental RVD improved renal functional responses, enhanced tissue remodeling, and decreased structural injury. This study supports critical pathogenic contribution of increased oxidative stress to renal injury and
scarring in RVD and suggests a role for
antioxidant strategies in preserving the atherosclerotic and ischemic kidney.