Mosaic distribution and segment-specific functions of nitric oxide synthase (NOS) isofroms in the kidney create substantial experimental difficulties in evaluating the role of NO in renal physiology and pathophysiology. Indeed, there is a growing ambiguity as to the role of NO and its metabolic product peroxinitrite (ONOO-)in the pathophysiology of acute renal failure (ARF). NO and ONOO- have been shown to mediate hypoxia-reperfusion injury in different organs including the kidney, while the inhibitors of NOS exhibit anti-inflammatory properties. Paradoxically, NOS inhibitors in in vitro experiments, protects renal tubular epithelium against hypoxic injury, whereas they invariably aggrevate renal dysfunction in different in vivo models of ARF. To reconcile these experimental differences solid observations based on the use of non-selective inhibitors, the principal investigator's laboratory has designed and tested antisense phosphorothioate oligodeoxynucleotides (AS-S-ODN) targeting various sequences of inducible (iNOS) cDNA. The data obtained both in vitro and in vivo provide evidence for cytoprotection afforded by AS-S-ODN to iNOS in ARF. The present proposal is aimed to investigate the topography and time-course of expression and activity of NOS isoforms in ischemic and endotoxic ARF and to design ODN constructs with improved site-specificity. The techniques to be used in this study include in vivo experiments in mice subjected to ischemic or endotoxic ARF, immunohistochemistry, Western blot analysis, an in situ hybridization of NOS isoforms, in situ monitoring of NO release by ischemic kidneys, use of animals with targeted disruption of iNOS and iNOS genes, as well as mice with acute knock-down of iNOS employing S-ODN strategy. In addition, conjugates of AS-S-ODN with cell-selective targeting sequences will be designed and tested in both ischemic and endotoxic models of ARF. It is anticipated that this work should elucidate site-specific expression and function of NOS isoforms, their respective role in injury and recovery from ischemia and endotoxemia, and offer novel therapeutic approaches for alieviating the cytotoxicity of NO and its intermediates, while enhancing the effects of NO on renal hemodynamics and reparative processes.
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