Antioxidant Intervention Blunts Renal Injury in Experimental Renovascular Disease

Abstract

Abstract. 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 ϭ 7), RVD daily supplemented with antioxidant vitamins C (1 g), and E (100 IU/kg) (RVDϩVitamins, n ϭ 7), or controls (normal, n ϭ 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 RVDϩVitamins (P Ͻ 0.05 versus RVD). RVDϩVitamins also showed increased renal expression of endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H-oxidase, nitrotyrosine, inducible-NOS, and NF-B, suggesting decreased superoxide abundance and inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVDϩVitamins 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.

Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

“…SOD1 activity was determined in vitro using a Superoxide Dismutase Assay kit from Cayman Chemicals according to the manufacturer's instructions (22). See SI Materials and Methods for more information.…”

Effects of Proteasome Inhibition on the Kidney in Experimental Hypercholesterolemia

“…Anesthesia was maintained with a mixture of ketamine (0.2 mg/kg per min) and xylazine (0.03 mg/kg per min), as previously detailed (3,4,16,19,20). In vivo electron-beam compute tomography (EBCT) studies were performed for assessment of single-kidney renal blood flow (RBF), GFR, and regional renal perfusion and repeated during suprarenal intra-aortic infusion of acetylcholine (Ach; 5 g/kg per min) to test endothelium-dependent responses, as described previously (3,4).…”

“…In line with these observations, emerging evidence supports the notion that proteasome inhibitors (PSI) may be vasculo-and tissue-protective (11,13). Notably, the UPS may also contribute to renal injury (14), and we recently observed its activation in the early stage of experimental renovascular disease (15,16). However, the potentially beneficial effects of PSI on the kidney in the early stage of atherogenesis, a proinflammatory condition associated with increased NF-B and UPS activation, remain unknown.…”

Collared Pecary (tayassu tajacu) as a new model of renal ischemic injury induced by clamping the renal artery

“…The renal ischemia induction model has previously been performed in animals such as rats 1 and pigs 5 to analyze the severity and extent of injury and to evaluate therapeutic treatments for secondary hypertension 6 .…”