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Soluble Epoxide Hydrolase Inhibition Protects the Kidney from Hypertension-Induced Damage

Xueying Zhao^*, Tatsuo Yamamoto^¶, John W. Newman^||, In-Hae Kim^||, Takaho Watanabe^||, Bruce D. Hammock^||, Janet Stewart^*, Jennifer S. Pollock^*,, David M. Pollock^*, and John D. Imig^*,

*Vascular Biology Center, Department of Physiology, Department of Pharmacology, Department of Surgery, Medical College of Georgia, Augusta; ^||Department of Entomology, and Cancer Center, University of California at Davis; and ^¶First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Correspondence to: Dr. John D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. Phone: 706-721-1901; Fax: 706-721-9799; E-mail: jdimig{at}mail.mcg.edu

ABSTRACT. Epoxyeicosatrienoic acids (EET) have antihypertensive and anti-inflammatory properties and play a role in the maintenance of renal vascular function. A novel approach to increase EET levels is to inhibit epoxide hydrolase enzymes that are responsible for conversion of biologically active EET to dihydroxyeicosatrienoic acids (DHET). We hypothesized that soluble epoxide hydrolase (SEH) inhibition would improve renal vascular function and ameliorate hypertension induced renal damage. Chronic administration of the specific SEH inhibitor 1-cyclohexyl-3-dodecylurea (CDU, 3 mg/d) for 10 d lowered BP in angiotensin hypertensive rats. The contribution of renal vascular SEH to afferent arteriolar function in angiotensin hypertension was also assessed. SEH protein expression was increased in renal microvessels from hypertensive rats. Although CDU did not change afferent arteriolar responsiveness to angiotensin in normotensive animals, CDU treatment significantly attenuated afferent arteriolar diameter responses to angiotensin in hypertensive kidneys from 51% ± 8% to 28% ± 7%. Protection of the renal vasculature and glomerulus during chronic CDU administration was demonstrated by histology. Urinary albumin excretion, an index of renal damage, was also lower in CDU-treated hypertensive rats. These data demonstrate that SEH inhibition has antihypertensive and renal vascular protective effects in angiotensin hypertension and suggests that SEH inhibitors may be a useful therapeutic intervention for cardiovascular diseases.

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