Role of Epoxyeicosatrienoic acid in diabetic nephropathy

Diabetic nephropathy (DN) is a major complication of diabetes mellitus and the leading cause of end-stage renal disease. The disease is manifested as microalbuminuria which further progresses to macroalbuminuria with an elevation in blood pressure and decline in glomerular filtration rate. Current treatments only slow the progression of DN; therefore, a novel strategy is needed to inhibit disease progression. Epoxyeicosatrienoic acids (EETs) are endothelium-derived hyperpolarizing factors with antihypertensive and anti-inflammatory actions. Because previous findings suggest that decreased EETs levels increased inflammation in non obese diabetic which could contribute in the pathogenesis of type 1 diabetes, a diminished EET anti-inflammatory action is a potential mechanism for the pathogenesis of DN. Thus, the aim of this project is to investigate the role of increasing EETs levels in halting the progression of DN. EETs are rapidly degraded by the soluble epoxide hydrolase enzyme (sEH) to less active or inactive dihydroxyeicosatrienoic (DHETs). EPHX2 is the gene responsible for sEH production. Inhibition of sEH reduces renal injury in diabetic hypertensive Rats. Thus, inhibition of sEH or EPHX2 gene deletion may also prevent the progression of DN. Preliminary data demonstrate that EPHX2 gene deletion improved afferent arteriolar relaxation to acetylcholine and decreased markers of inflammation and renal injury in streptozotocin-induced diabetic mice compared to wild type (WT) diabetic mice. Moreover, renal nuclear factor kappa B (NFKappaB) activity decreased and the antioxidant hemeoxygenase-1 (HO-1) expression was significantly up-regulated in EPHX2 -/- compared to WT diabetic mice. Studies have shown that EETs prevented leukocyte adhesion to the vascular wall by inhibition of NFKB. Thus, the hypothesis of this proposal is EETs reduce renal inflammation and damage in type 1 diabetes via the inhibition of NFkB and the activation of HO-1 antioxidant mechanisms. Using EPHX2-/- mice and pharmacological inhibition of sEH, the following aims will be tested; Aim 1: To test the hypothesis that increasing EETs levels reduces kidney inflammation and damage via inhibiting NFkB in streptozotocin-induced type 1 diabetic mice. Aim 2: To test the hypothesis that EETs induction of HO-1 contributes to reduced renal damage via inhibition of NADPH-derived superoxide production in type 1 diabetic mice. (AHA Program: Scientist Development Grant)