RENAL IMMUNE INJURY--NO/EICOSANOID INTERACTIONS

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DESCRIPTION (Adapted from Investigator's Abstract): The goal of these studies is to examine interactions between arachidonic acid pathways and nitric oxide pathways in renal immune injury. Previous studies by the Principal Investigator, as well as others, have demonstrated that in experimental models of renal immune injury, both of these pathways are activated and result in synthesis of proinflammatory eicosanoids and generation of nitric oxide in isolated glomeruli. Furthermore, there is evidence that infiltrating activated macrophages are a key site where both are generated. Eicosanoid species produced include both cyclooxygenase and 5-lipoxygenase metabolides. It is postulated that the vasoconstrictive eicosanoids produced may be important contributors to renal vasoconstriction and structural damage to the glomerulus. The Principal Investigator also postulates that nitric oxide may play a detrimental role in glomerular and inflammatory injury due to generation of peroxynitrite secondary to interactions of oxygen free radical species with nitric oxide, and hypothesizes that the induction of iNOS may have deleterious consequences due to this generation of nitric oxide in inflammatory renal injury. These studies are also motivated by evidence that nitric oxide may activate cyclooxygenase in vivo and in vitro. Therefore, the hypotheses are: 1) In glomerular immune-injury NO generated as a result of iNOS activation regulates synthesis of pro-inflammatory eicosanoids, and these eicosanoids modulate expression and activity of iNOS, and 2) In glomerular immune-injury, NO preserves renal hemodynamic function and activation of iNOS promotes glomerular cell injury. There are four specific aims in this proposal. The first specific aim will examine whether nitric oxide derived from iNOS activation by glomerular inflammatory injury will regulate cyclooxygenase activity and also whether there is an effect to activate lipoxygenase activity. The second specific aim will determine whether eicosanoids will modulate iNOS expression and generation of iNOS derived nitric oxide. The third specific aim will examine whether in glomerular immune-injury NO serves a beneficial function to preserve renal blood flow in glomerular filtration, and the fourth specific aim will determine whether in glomerular immune-injury NO may serve a harmful function via interaction of NO with superoxide in formation of peroxynitrite or similar oxidants. It is anticipated that the observations will provide new insights in the pathobiology of glomerulonephritis.