Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia

Abstract

Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability of intrarenal nitric oxide is not known. We tested the hypothesis that oxidative stress might contribute to the endothelial dysfunction and glomerular hemodynamic changes that occur with hyperuricemia. Hyperuricemia was induced in Sprague-Dawley rats by administration of the uricase inhibitor, oxonic acid (750 mg/kg per day). The superoxide scavenger, tempol (15 mg/kg per day), or placebo was administered simultaneously with the oxonic acid. All groups were evaluated throughout a 5-wk period. Kidneys were fixed by perfusion and afferent arteriole morphology, and tubulointerstitial 3-nitrotyrosine, 4-hydroxynonenal, NOX-4 subunit of renal NADPH-oxidase, and angiotensin II were quantified. Hyperuricemia induced intrarenal oxidative stress, increased expression of NOX-4 and angiotensin II, and decreased nitric oxide bioavailability, systemic hypertension, renal vasoconstriction, and afferent arteriolopathy. Tempol treatment reversed the systemic and renal alterations induced by hyperuricemia despite equivalent hyperuricemia. Moreover, because tempol prevented the development of preglomerular damage and decreased blood pressure, glomerular pressure was maintained at normal values as well. Mild hyperuricemia induced by uricase inhibition causes intrarenal oxidative stress, which contributes to the development of the systemic hypertension and the renal abnormalities induced by increased uric acid. Scavenging of the superoxide anion in this setting attenuates the adverse effects induced by hyperuricemia.

Fig. 1.

Effect of antioxidant therapy with tempol to oxonic acid (OA)-treated rats on uric acid, blood pressure, glomerular filtration rate (GFR), urinary excretion of nitric oxide (NO) metabolites (NO₂⁻/NO₃⁻), single nephron GFR, and glomerular pressure.

Fig. 2.

Effect of antioxidant therapy with tempol to OA-treated rats on afferent arteriole morphology, tubulointerstitial markers of oxidative stress, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE), and NOX-4 and angiotensin II (AII) expressions in normal, oxonic acid, and oxonic acid + tempol-treated rats.

Fig. 3.

Representative micrographs of afferent arteriole morphology, tubulointerstitial markers of oxidative stress, 3-NT and 4-HNE, and NOX-4 and AII expressions in normal, oxonic acid and oxonic acid + tempol-treated rats (all 400×, except NOX-4, 200×).