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1 Department of Internal Medicine-Division of Hypertension, Mayo Clinic, Rochester, MN, USA
2 Department of Internal Medicine-Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
3 Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN, USA
4 Department of Internal Medicine-Division of Hypertension, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine-Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: lerman.lilach{at}mayo.edu.
Background: Reactive oxygen species (ROS) can modulate renal hemodynamics and function both directly, by leading to vasoconstriction, and indirectly, by inducing renal inflammation and tissue growth. The involvement of oxidative-stress in the pathogenesis of renovascular disease (RVD) is increasingly recognized, but the relative contribution of longterm tissue injury to renal dysfunction remains unclear. We hypothesized that functional and structural alterations elicited by oxidative stress in RVD would be more effectively modulated by chronic than by acute antioxidant intervention. Methods: Renal hemodynamics and function were quantified in-vivo in pigs using electron-beam CT at baseline and after vasoactive challenge (Ach and sodium-nitroprusside), after 12 weeks of RVD (simulated by concurrent hypercholesterolemia and renal-artery-stenosis, n=7), RVD acutely infused with the SODmimetic Tempol (RVD+Tempol, n=7), RVD chronically 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 immunoblotting and immunohistochemistry. Results: Basal renal-blood-flow (RBF) and glomerular-filtration-rate (GFR) were similarly decreased in all RVD groups. Ach-stimulated RBF remained unchanged in RVD, increased in RVD+Tempol, but further increased (similarly to normal) in RVD+Vitamins (p<0.05 vs. RVD). Furthermore, RVD+Vitamins also showed decreased presence of superoxide anion, NAD(P)H-oxidase and nitrotyrosine expression, increased endothelial-nitric-oxide-synthase expression, and attenuated renal fibrosis. Conclusion: Chronic antioxidant intervention in early RVD improved renal hemodynamic responses more effectively than acute intervention, likely due to increased nitricoxide bioavailability and decreased structural injury. These suggest that chronic tissue changes play an important role in renal compromise mediated by oxidative-stress in RVD.
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