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Chronic kidney disease (CKD) disproportionately affects African Americans, who are four times more likely to progress to end-stage renal disease (ESRD) than Caucasians. The genes and mechanisms responsible for this important racial health disparity are largely unknown. Studies performed over the past ten years have indicated that cytochrome P450 (CYP) metabolites of arachidonic acid, 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), play an important role in the regulation of renal tubular function and vascular tone, and that abnormalities these lipid mediators may contribute to the development of hypertension and renal injury. Pharmacologic inhibition or knockout of soluble epoxide hydrolase (sEH), which converts EETs to dihyroxyeicosatrienoic acid (DHET), has also been shown to attenuate the development of hypertension and renal injury in various animal models. Subsequent studies have identified associations with polymorphisms in CYP4A and 4F genes that produce 20-HETE and sEH with hypertension, stroke, and coronary artery disease in a variety of human populations. In particular, a genetic linkage study in African Americans showed an association of the CYP4A11 F434S sequence variant with mortality and development of ESRD. However, no study to date has attempted to measure the levels of 20-HETE, EETs or DHETs in patients with genetic polymorphisms or to determine the relationships among eicosanoid profiles and progression of hypertension and CKD.
In preliminary work, we have established sensitive mass spectroscopy (LC/MS/MS) techniques to measure urinary eicosanoid levels and found that urinary 20-HETE levels directly correlate with glomerular filtration (eGFR) and varying degrees of CKD. These studies establish that we have the tools to measure eicosanoids in patient populations and suggest that 20-HETE may play a protective role in CKD populations. We propose to conduct longitudinal studies relating CYP genetic variants to urinary eicosanoids and the development and progression of hypertension and CKD in two African-American cohorts, totaling 1,000 participants: the University of Mississippi CKD Clinic(Aim 1), and the Jackson Heart Study (Aim 2), and we also will test the relationship of these factors with the progression and development of proteinuria and diabetic nephropathy (Aim 3).
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