NITRIC OXIDE IN RENAL DISEASE

DESCRIPTION (Adapted from the Applicant's Abstract): Ischemia/reperfusion injury is caused by activation of cytotoxic and inflammatory cascades during the reperfusion period. Injury in experimental animals can be modestly decreased by inhibition of either of these two pathways. They recently found the a-MSH protects against severe renal ischemia/reperfusion injury, even when started during the reperfusion period. a-MSH is a neuropeptide with broad anti-inflammatory properties. They found that a-MSH inhibits the synthesis of cytokines, chemoattractive chemokines and NO. It is not known why a-MSH is so effective in preventing ischemia/reperfusion injury. They hypothesize that a-MSH prevents the maladaptive activation of both the cytotoxic (NO) and inflammatory (neutrophile) cascade. They will investigate the following Specific Aims: In Aim #1, they will define the spectrum of activity of a-MSH in treating ischemia/reperfusion injury. They will determine when a-MSH is active during the reperfusion period and if a-MSH accelerates recovery from established renal failure. In Aim #2, they will localize the MSH receptors to specific portions of the nephron and vasculature using in situ hybridization and RT/PCR. They will also determine where a-MSH is produced. In Aim #3, they will determine the effect of a-MSH on ischemia induced cytotoxicity mediated by NO. They have preliminary evidence that a-MSH inhibits the production of iNOS during ischemia/reperfusion. They will determine if NO is responsible for tissue injury in kidneys, isolated perfused kidneys and isolated tubules subjected to ischemia. In Aim #4, they will determine the effect of a-MSH on the ischemia-induced injury mediated by neutrophiles. They will study the effect of a-MSH on neutrophile infiltration, expression of renal chemattractants and endothelial cell adhesion molecules in the ischemic models.