Mechanisms of Renoprotection by Soluble Epoxide Hydrolase Inhibition

Investigator: Deanna L. Kroetz, PhD
Sponsor: NIH National Institute of Diabetes and Digestive and Kidney Diseases

Location(s): United States


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.  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.  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.