Affiliation:
1. Department of Medicine, University of Colorado Health Sciences Center, Denver 80262;
2. Department of Medicine, Baylor College of Medicine, Houston, Texas 77030; and
3. Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206
Abstract
Acute renal failure (ARF) during sepsis is associated with increased nitric oxide (NO) and oxygen radicals, including superoxide (O[Formula: see text]). Because O[Formula: see text] reacts with NO in a rapid manner, it plays an important role in modulating NO levels. Therefore, scavenging of O[Formula: see text] 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[Formula: see text] in the kidney. We hypothesized that during endotoxemic ARF, EC-SOD is decreased in the kidney, resulting in increased O[Formula: see text] 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 μl/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 μl/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.
Publisher
American Physiological Society
Cited by
144 articles.
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