title: 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.
authors.affiliation: Department of Nephrology, INC Ignacio Chávez, Juan Badiano 1. 14080. Mexico City, Mexico. lgsanchezlozada@gmail.com
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sánchez-Lozada
authors.forename: Virgilia
authors.initials: V
authors.lastname: Soto
authors.forename: Edilia
authors.initials: E
authors.lastname: Tapia
authors.forename: Carmen
authors.initials: C
authors.lastname: Avila-Casado
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Martha
authors.initials: M
authors.lastname: Franco
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rodríguez-Iturbe
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001160:Arterioles / Q000502:physiology; D001835:Body Weight; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000502:physiology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism*; D033461:Hyperuricemia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010094:Oxonic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; C002744:3-nitrotyrosine; D014443:Tyrosine; D010094:Oxonic Acid; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; C027576:4-hydroxy-2-nonenal; C001803:tempol