ascorbic-acid and Renal-Artery-Obstruction

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 long-term 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. Renal hemodynamics and function were quantified in vivo in pigs using electron-beam computed tomography at baseline and after vasoactive challenge (ACh and sodium nitroprusside); after 12 wk of RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7); RVD acutely infused with the SOD-mimetic tempol (RVD+tempol, n = 7); RVD chronically supplemented with antioxidant vitamins C (1 g) and E (100 IU/kg; RVD+vitamins, n = 7); or control (normal, n = 7). Renal tissue was studied ex vivo using immunoblotting and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate 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 a decreased presence of superoxide anion, decreased NAD(P)H-oxidase and nitrotyrosine expression, increased endothelial nitric oxide synthase expression, and attenuated renal fibrosis. Chronic antioxidant intervention in early RVD improved renal hemodynamic responses more effectively than acute intervention, likely due to increased nitric oxide bioavailability and decreased structural injury. These suggest that chronic tissue changes play an important role in renal compromise mediated by oxidative stress in RVD.

Topics: Acetylcholine; Acute Disease; Animals; Antioxidants; Ascorbic Acid; Blotting, Western; Chronic Disease; Cyclic N-Oxides; Glomerular Filtration Rate; Hypertension, Renovascular; In Vitro Techniques; Kidney Function Tests; Kidney Tubules; Nitroprusside; Oxidative Stress; Renal Artery Obstruction; Renal Circulation; Spin Labels; Superoxide Dismutase; Swine; Tomography, X-Ray Computed; Vasodilator Agents; Vitamin E

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.

Topics: Acetylcholine; Animals; Antioxidants; Ascorbic Acid; Fibrosis; Kidney; Nephritis; Nitroprusside; Oxidation-Reduction; Renal Artery Obstruction; Swine; Vitamin E

Coronary endothelial dysfunction is associated with an increase in cardiac events. Hypercholesterolemia (HC) and hypertension (HT) are both associated with endothelial dysfunction, and their coexistence is associated with an increased incidence of cardiac events in epidemiological studies. However, pathogenic mechanisms are poorly understood. Here we studied the effects of coexisting HC and HT on coronary endothelial function.. Four groups of pigs were studied after 12 weeks of a normal diet (n=9), a 2% HC diet (n=9), HT (achieved by unilateral renal artery stenosis, n=8), or HC+HT (n=6). Coronary endothelial function was tested, in epicardial arteries and arterioles, by using organ chamber techniques. Oxidative stress was measured in coronary artery tissue. Vasodilatory response to bradykinin and calcium ionophore was significantly impaired in animals with HC+HT compared with each risk factor alone (P<0.05 for both). In animals with coexistent HC and HT, the increase in oxidative stress was more pronounced compared with each risk factor alone (P<0.05). Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.. These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist.

Topics: Animals; Antioxidants; Ascorbic Acid; Bradykinin; Calcimycin; Coronary Artery Disease; Coronary Vessels; Cyclic GMP; Diet, Atherogenic; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Hypercholesterolemia; Hypertension, Renovascular; Lipids; Nitric Oxide; Nitroprusside; Oxidative Stress; Renal Artery Obstruction; Renin; Substance P; Swine; Vasodilator Agents; Vitamin E

Renal artery stenosis (RAS) may lead to renal injury, partly mediated through increased oxidative stress. However, the potential effects of chronic oral antioxidant intervention on the stenotic kidney remain unknown. This study was designed to test the hypothesis that chronic antioxidant vitamin supplementation in RAS would preserve renal function and structure. Single-kidney hemodynamics and function were quantified in vivo in pigs using electron-beam CT after 12 weeks of unilateral RAS (n=7), a similar degree of RAS orally supplemented with vitamins C (1 g) and E (100 IU/kg) (RAS+Vitamins, n=7), or controls (normal, n=7). Renal tissue was studied ex vivo using Western blotting and immunohistochemistry. Mean arterial pressure was similarly elevated in both RAS groups, while ischemic renal volume and glomerular filtration rate were similarly reduced. Renal blood flow was decreased in RAS compared with normal (326.5+/-99.9 versus 553.4+/-48.7 mL/min, respectively, P=0.01), but preserved in RAS+Vitamins (485.2+/-104.1 mL/min, P=0.3 versus normal). The marked increase in the expression of the NADPH-oxidase subunits p47phox and p67phox, nitrotyrosine, endothelial and inducible nitric oxide synthase, and nuclear factor-kappaB observed in RAS (P<0.05 versus normal) was normalized in RAS+Vitamins (P>0.1). Furthermore, trichrome staining and the expression of transforming growth factor-beta and tissue inhibitor of matrix-metalloproteinase-1 were also decreased in RAS+Vitamins. In conclusion, chronic blockade of the oxidative stress pathway in RAS using antioxidant vitamins improved renal hemodynamics and decreased oxidative stress, inflammation, and fibrosis in the ischemic kidney. These observations underscore the involvement of oxidative stress in renal injury in RAS and support a role for antioxidant vitamins in preserving the ischemic kidney.

Topics: Animals; Antioxidants; Ascorbic Acid; Fibrosis; Hemodynamics; Inflammation; Kidney; Oxidation-Reduction; Oxidative Stress; Regional Blood Flow; Renal Artery Obstruction; Swine; Vitamin E

Topics: Adult; Aged; Aneurysm; Ascorbic Acid; Female; Glomerular Filtration Rate; Humans; Hydronephrosis; Hypertension, Renal; Iodine Radioisotopes; Iodohippuric Acid; Isotope Labeling; Kidney; Kidney Calculi; Kidney Diseases, Cystic; Kidney Neoplasms; Male; Middle Aged; Pyelonephritis; Quality Control; Radioisotope Renography; Renal Artery; Renal Artery Obstruction; Technetium; Urinary Calculi