Ischemic acute renal failure remains a common cause of renal failure in the hospital setting. In spite of substantial investigation, the prognosis for this type of renal failure has not significantly improved. We and others have shown that complement activation is an important event in the development of ischemic acute renal failure in mice. The proposed studies aim to analyze the mechanisms of complement activation and complement dependent injury in models of ischemic acute renal failure. Experiments will also be conducted to determine whether a newly created inhibitor of the alternative complement pathway is of therapeutic benefit in these models of injury. Given the complexity of ischemic injury in the kidney, several in vivo and in vitro models will be used. These include the in vivo induction of ischemic acute renal failure in mice, and subjection of freshly isolated renal tubules to hypoxia in the presence or absence of complement factors. Many of the in vivo experiments will utilize mice that are deficient in specific complement activation pathway components or in the inhibitors of complement (i.e. knockout mice). The techniques used to measure the endpoints of these experiments include assays for serum urea nitrogen, light microscopy, immunofluorescence of cells in culture and of tissue sections, ELISA, Westem blot analysis, gene array analysis, and quantitative RT-PC1L In addition, some unique assays developed by our collaborators will be utilized, such as a method of measuring caspase activation. These experiments are designed to analyze in depth the complement dependent mechanisms of injury which occur during renal ischemia/reperfusion. The techniques used will utilize the expertise of experts in the fields of complement biology as well as acute renal failure. The purpose of these studies is to ameliorate ischemic ARF by blocking these pathogenic events, and to develop strategies for decreasing the morbidity and mortality associated with ischemic ARF in humans.
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