title: Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure.
abstract: Acute renal failure (ARF) during sepsis is associated with increased nitric oxide (NO) and oxygen radicals, including superoxide (O(2)(-)). Because O(2)(-) reacts with NO in a rapid manner, it plays an important role in modulating NO levels. Therefore, scavenging of O(2)(-) by superoxide dismutase (SOD) may be critical for preserving NO bioavailability. In mice, substantial renal extracellular SOD (EC-SOD) expression implies its important role in scavenging O(2)(-) in the kidney. We hypothesized that during endotoxemic ARF, EC-SOD is decreased in the kidney, resulting in increased O(2)(-) and thus decreased vascular NO bioavailability with resultant renal vasoconstriction and ARF. In the present study, normotensive endotoxemic ARF was induced in mice using lipopolysaccharide (LPS; 5 mg/kg ip). Sixteen hours after LPS, glomerular filtration rate (GFR; 50 +/- 16 vs. 229 +/- 21 microl/min, n = 8, P < 0.01) and renal blood flow (RBF; 0.61 +/- 0.10 vs. 0.86 +/- 0.05 ml/min, n = 8, P < 0.05) were subsequently decreased. EC-SOD mRNA and protein expression in endotoxemic kidneys were decreased at 16 h compared with controls. A catalytic antioxidant, metalloporphyrin, reversed the deleterious effects of endotoxemia on renal function as GFR (182 +/- 40 vs. 50 +/- 16 microl/min, n = 6, P < 0.01) and RBF (1.08 +/- 0.10 vs. 0.61 +/- 0.10 ml/min, n = 6, P < 0.05) were preserved. Similar results were obtained with tempol, a chemically dissimilar antioxidant. Specific inhibition of inducible nitric oxide synthase (iNOS), l-N(6)-(1-iminoethyl)-lysine, reversed the renal protective effect on GFR and RBF observed with antioxidant treatment during endotoxemia. In summary, renal EC-SOD expression is decreased during endotoxemia. Antioxidant therapy preserved GFR and RBF during endotoxemia. The reversal of this protective effect by inhibition of iNOS suggests the importance of the bioavailability of NO for preservation of renal function during early endotoxemia.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Suparoek
authors.initials: S
authors.lastname: Jittikanont
authors.forename: Sandor A
authors.initials: SA
authors.lastname: Falk
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Gengaro
authors.forename: Brian D
authors.initials: BD
authors.lastname: Poole
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017597:Renal Blood Flow, Effective / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase