Despite advances in supportive care, acute renal failure (ARF) is a morbid disease with high mortality rates that have not changed in 50 years. Treatment of human ARF has been hampered by ineffective drugs; dialysis may prolong ARF. We recently found that the anti-inflammatory cytokine alpha-melanocyte stimulating hormone (alpha-MSH) prevents damage from renal ischemia-reperfusion injury even when started 6 hr after ischemia. In preliminary experiments, we found that the effects of alpha-MSH may be at least in part mediated by the anti-inflammatory cytokine IL-10, that IL-10 prevents ischemic renal damage, and that IL-10 knock-out mice are more sensitive to ischemia. These surprising results caused us to hypothesize a new renal anti-inflammatory cascade ( alpha-MSH/IL-10 axis ): alpha-MSH activates an endogenous IL-10 pathway that limits ischemic injury. Because IL-10 may act more directly than alpha-MSH, IL-10 might be effective later after injury. Alternatively, IL-10 and alpha-MSH may act synergistically to present renal injury. We will pursue the following aims: In Aim 1, we will characterize the protective role of endogenous IL-10 in renal ischemic injury and following alpha-MSH. We will determine if renal IL-10 is sufficient to protect against ischemic injury. In Aim 2, we will determine the location and regulation of IL-10 production. We will study if IL-10 is regulated by ischemia, alpha-MSH, and other agents. In Aim 3, we will determine when exogenous IL-10 is effective in renal ischemia, and if IL-10 enhances recovery from established renal injury. We will determine if IL-10 and alpha-MSH act synergistically to prevent renal injury. In Aim 4, we will characerize the mechanism of IL-10 action and the location of IL-10 receptors. We will determine if IL-10 interrupts maladaptive inflammatory or cytotoxic pathways that amplify renal injury. These studies will define how the alpha-MSH/IL-10 axis protects against renal injury, and aid the long-term goal of the project that is to further our understanding of this endogenous protective pathway with an aim to develop novel therapeutic agents to extend the window of time before ischemic injury becomes irreversible and to restore function in organs that sustain ischemic injury in humans.