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1 Physiology, Medical College of Georgia, Augusta, Georgia, United States; Renal, Second Affiliated Hospital of Sun Yat-Sen University, Guangdong, China
2 Entomology and Cancer Center, University of California, Davis, California, United States
3 Renal, Second Affiliated Hospital of Sun Yat-Sen University, Guangdong, China
4 Division of Nephrology, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, United States
5 Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States
6 Physiology, Medical College of Georgia, Augusta, Georgia, United States
* To whom correspondence should be addressed. E-mail: mwang{at}manil.mcg.edu.
Since epoxyeicosatrienoic acids (EETs) affect sodium reabsorption in renal tubules and dilate the renal vasculature, we have examined their effects on renal hemodynamics and sodium balance in male rats fed a high-fat (HF) diet by fenofibrate, a peroxisome proliferator-activated receptor 
(PPAR ) agonist and an inducer of CYP epoxygenases; by N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH), a selective EET biosynthesis inhibitor; and by 12-(3-adamantane-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of soluble epoxide hydrolase. As compared with vehicle-treated control groups, rats treated with fenofibrate (30 mg/kg/day, i.g., for 2 weeks) or AUDA (50 mg/L in drinking water for 2 weeks) had lower mean arterial pressure, renal vascular resistance, and glomerular filtration rate, but higher renal blood flow. In addition, both fenofibrate and AUDA treatment decreased cumulative sodium balance in HF rats. Combined treatment with MSPPOH (20 mg/kg/day, iv, for 2 weeks) and fenofibrate reversed renal hemodynamics and sodium balance to the levels in control HF rats. Moreover, fenofibrate caused a 3-fold increase in renal cortical CYP epoxygenase activity, whereas the elevation of this activity by fenofibrate was attenuated by MSPPOH. Western blot analysis showed that fenofibrate induced the expression of CYP epoxygenases in renal cortex and microvessels, and that the induction effect of fenofibrate was blocked by MSPPOH. These results demonstrate that increasing expression of CYP epoxygenases by fenofibrate and the stabilization of EET production by AUDA in the kidneys cause renal vascular dilation and reduce sodium retention, contributing to the improvement of abnormal renal hemodynamics and hypertension in HF rats.
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