Acute renal failure claims 25,000 lives annually. This project explores the use of docosahexaenoic acid (DHA) in the treatment of ischemic acute renal failure. DHA is a 22 carbon, omega-3 fatty acid with 6 double bonds. Our current proposal is based on two striking effects of DHA. First, we find that docosahexaenoic acid (DHA) prevents damage from ischemia/reperfusion injury in a murine model. All of the control animals died of acute renal failure at 72 hours after clamping both renal arteries for 30 minutes, but only 15 percent of the DHA-treated animals. Second, we find that DHA inhibits activation of the gene for inducible nitric oxide synthase (iNOS) by macrophages in vitro. This enzyme produces large quantities of the cytotoxic molecule nitric oxide which contribute to renal injury after ischemia. Furthermore, we find that DHA inhibits iNOS gene activation by inhibiting the action of the transcription factor IRF-1. IRF-1 is activated by cellular stress and coordinates a stress response. This includes activation of genes for endothelial adhesion molecules which regulate inflammation, for cytokines and chemokines and iNOS. In this proposal, we will explore DHA as a potential therapy of acute renal failure and test the hypothesis that DHA inhibits the maladaptive stress response by inhibiting the transcription factor IRF-1. We will determine if DHA inhibits the inflammatory response to ischemia, and if DHA inhibits maladaptive responses of renal tubule cells to ischemic stress. The latter includes activation of iNOS. We will test the prediction that DHA ameliorates ischemic acute renal failure by inhibiting IRF-1 action. We will compare the susceptibility of IRF-1 knockout mice and plus/plus control mice to renal ischemia. We will also use IRF-1 antisense therapy to treat ischemic acute renal failure. Others have developed phosphorothioate antisense oligonucleotides for IRF-1, and the kidney, by virtue of the propensity of the proximal tubule to absorb polyanions such as antisense oligonucleotides, is an ideal target for antisense therapy.
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