Mechanisms of Renoprotection by Soluble Epoxide Hydrolase Inhibition

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DESCRIPTION (provided by applicant): Soluble epoxide hydrolase (sEH) is a dual function Phase II metabolic enzyme that catalyzes the hydrolysis of both xenobiotic and endobiotic epoxides. sEH metabolism of xenobiotic epoxides often results in their detoxification and accelerated elimination, whereas that of endobiotic epoxides is generally associated with attenuation of epoxide biological properties. Endogenous substrates of sEH are unsaturated fatty acid epoxides, including epoxyeicosatrienoic acids (EETs), which are major products of cytochrome P450 (CYP)-catalyzed metabolism of arachidonic acid, an essential fatty acid nutrient. The hydrolysis of EETs to their corresponding dihydroxyeicosatrienoic acids by sEH has recently emerged as a key factor controlling the biological effects of EETs, including vasoactive, anti- inflammatory and anti-apoptotic effects. Recent preliminary data from our laboratory shows that chemical or genetic disruption of sEH activity protects against acute kidney injury induced by cisplatin treatment. Specifically, the protective effects of sEH inhibition are associated with decreased inflammation and a dramatic attenuation of apoptosis. The focus of this proposal is to understand the mechanistic basis for the renoprotection afforded by disruption of sEH activity. Three specific aims are proposed to test the overall hypothesis that inhibition of sEH protects against acute kidney injury. The first aim will identify the signaling pathways involved in the renoprotective effect of sEH inhibition in a cisplatin model of acute kidney injury. The role of NF-?B and PPAR? signaling will be examined, particularly with respect to the anti-inflammatory effects of sEH inhibition in acute kidney injury. The effect of sEH inhibition on the intrinsic mitochondrial apoptotic pathway will also be investigated. Studies proposed for the second aim will extend our findings in a cisplatin model of acute kidney injury to additional models which involve different renal insults and signaling pathways. The renoprotective properties of sEH inhibition will be studied in both a unilateral ureter ligation model and in ischemia/reperfusion. Finally, the third aim will directly test the ability of EETs to protect against drug- or ischemia-induced renal cell injury, using cultured renal epithelial cells. The relative contribution of vascular versus tubular formed fatty acid epoxides in renoprotection will also be tested, using mouse strains with tissue specific overexpression or disruption of CYP epoxygenases and sEH. A combination of chemical and genetic tools to modulate sEH activity and EET production provide the critical framework to advance our preliminary observation of renoprotection associated with sEH inhibition. A long term goal of these studies is to develop strategies for the therapeutic modulation of sEH for the prevention and treatment of acute kidney injury. The general nature of the anti-inflammatory and anti-apoptotic effects of sEH inhibition will make our findings more broadly relevant to diseases affecting other organs as well. PUBLIC HEALTH RELEVANCE: Acute kidney injury is a complex syndrome occurring in 20% to 30% of critically ill patients, and is associated with increased mortality, hospitalization, use of healthcare resources, and costs. Despite decades of research in animal models, effective strategies for prevention of acute kidney injury have yet to make it to the clinic. The studies proposed in this application will explore a novel pathway for protection against acute kidney injury which exploits an abundant renal fatty acid epoxide with established roles in inflammation and apoptosis.