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      Gentamicin Decreases Guanylyl Cyclase Activity in Rat Glomerulus

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          Background: Effects of gentamicin (GM) on the local natriuretic peptide (NP) and nitric oxide (NO) systems in the kidney were investigated. Methods: Male Sprague-Dawley rats (180–200 g) were intramuscularly injected with GM (100 mg/kg/day) for 5 days. The expression of NO synthase (NOS) isoforms was determined by Western blot analysis, and that of NPs by real-time polymerase chain reaction. The activity of guanylyl cyclase was also determined by the amount of guanosine 3′,5′-cyclic monophosphate (cGMP) generated in responses to atrial natriuretic peptide (ANP) or sodium nitroprusside (SNP). Results: GM treatment resulted in renal failure in association with increases in urinary flow and the fractional excretion of sodium. Accordingly, the expression of inducible NOS was increased in the cortex, while that of endothelial NOS remained unchanged. The urinary excretion of NO metabolites was increased. The expression of ANP, brain natriuretic peptide and C-type natriuretic peptide mRNA was increased in the kidney. The cGMP production provoked by either ANP or SNP was decreased in the glomerulus, but not in the papilla. Conclusion: GM-induced nephropathy may be causally related with decreased guanylyl cyclase activities in the glomerulus.

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          Most cited references 15

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          Inflammation and Stroke: Putative Role for Cytokines, Adhesion Molecules and iNOS in Brain Response to Ischemia

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            In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia.

            Gene products of all three distinct nitric oxide synthases are present in the mammalian kidney. This mosaic topography of nitric oxide synthase (NOS) isoforms probably reflects distinct functional role played by each enzyme. While nitric oxide (NO) is cytotoxic to isolated renal tubules, inhibition of NO production in vivo invariably results in the aggravation of renal dysfunction in various models of acute renal failure. We reasoned that the existing ambiguity on the role of nitric oxide in acute renal failure is in part due to the lack of selective NOS inhibitors. Phosphorothioated derivatives of antisense oligodeoxynucleotides targeting a conserved sequence within the open reading frame of the cDNA encoding the inducible NOS (iNOS) were designed to produce a selective knock-down of this enzyme. In vivo use of these antisense constructs attenuated acute renal failure in rats subjected to renal ischemia. This effect was due, at least in part, to the rescue of tubular epithelium from lethal injury. Application of antisense constructs did not affect endothelial NOS, as evidenced by a spared NO release after the infusion of bradykinin during in vivo monitoring with an NO-selective microelectrode. In conclusion, the data provide direct evidence for the cytotoxic effects of NO produced via iNOS in the course of ischemic acute renal failure, and offer a novel method to selectively prevent the induction of this enzyme.
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              Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury.

              Nitric oxide (NO), among several other functions, may play a role in hypoxia and reoxygenation injury due to its free radical nature and high reactivity with the superoxide radical to yield peroxynitrite, an oxidant molecule. The present study was undertaken to evaluate a potential role for NO, either endogenous or exogenous, in a model of hypoxia/reoxygenation (H/R) in freshly isolated rat proximal tubules. NO synthase activity, as assessed by conversion of L-[3H]arginine to L-[3H]citrulline, was detected in normoxic tubules. This activity could be inhibited by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and was stimulated by 15 min of hypoxia. The injury in proximal tubules caused by 15 min of hypoxia followed by 35 min of reoxygenation was completely prevented by L-NAME as assessed by release of lactate dehydrogenase, whereas D-NAME, which does not inhibit NO synthase, had no effect. In contrast, L-arginine (NO substrate) enhanced the H/R injury. These effects were paralleled by nitrite/nitrate production. In separate experiments, the addition of sodium nitroprusside, a NO donor, to proximal tubules enhanced the H/R injury; this effect could be blocked by hemoglobin, a NO scavenger. Also, addition of nitroprusside reversed L-NAME protection against H/R injury. These results demonstrate that NO is synthesized in rat proximal tubules and participates as one of the mediators in rat tubular H/R injury.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                April 2007
                20 February 2007
                : 30
                : 2
                : 81-87
                Departments of aInternal Medicine and bPhysiology, Chonnam National University Medical School, Gwangju, and cDepartment of Physiology, Chonbuk National University Medical School, Jeonju, Korea
                100010 Kidney Blood Press Res 2007;30:81–87
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 2, References: 31, Pages: 7
                Original Paper


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