: Hypertension that develops following the long-term administration of initially subpressor doses of angiotensin II in rats has many of the same renal and vascular changes that are associated with human essential hypertension. In the past five years, we have provided compelling evidence that CYP45O-derived epoxyeicosatrienoic acids (EETs) have anti-hypertensive properties and play a part in the maintenance of renal microvascular function. A novel approach to increase EET levels is to inhibit epoxide hydrolase enzymes that are responsible for the conversion of the biologically active EETs to dihydroxyeicosatrienoic acids (DHETs) that are void of effects on the preglomerular vasculature. Recently, a role for soluble epoxide hydrolase (sEH) in the long-term control of arterial blood pressure and the pathogenesis of experimental hypertension has been proposed. Preliminary studies in our laboratory demonstrate increased kidney sEH protein expression during angiotensin II hypertension. In addition, we have observed a decrease in arterial blood pressure in angiotensin II hypertension following administration of a highly selective sEH inhibitor. Based on these observations, we hypothesis that during the development of hypertension increased kidney sEH will decrease kidney EET levels which contributes to increased renal microvascular reactivity, blood pressure and renal vascular injury. We will directly determine the involvement of epoxide hydrolases to the excessive preglomerular vasoconstriction during the development of angiotensin II hypertension using the juxtamedullary nephron preparation. We will also determine renal microvascular EET and DHET levels and the regulation of kidney epoxide hydrolase enzymes during hypertension. The proposed studies will employ newly developed highly selective epoxide hydrolase inhibitors to determine their ability to lower arterial blood pressure and improve renal microvascular function in angiotensin II hypertension. Collectively, these studies will provide a comprehensive understanding of epoxide hydrolases in the long-term regulation of blood pressure and renal hemodynamic function during angiotensin II hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Barouch, Winifred
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Georgia (MCG)
Physical Medicine & Rehab
Schools of Medicine
United States
Zip Code
Deng, Bing-Qing; Luo, Ying; Kang, Xin et al. (2017) Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3? signaling. Proc Natl Acad Sci U S A 114:12608-12613
Hwang, Sung Hee; Wagner, Karen; Xu, Jian et al. (2017) Chemical synthesis and biological evaluation of ?-hydroxy polyunsaturated fatty acids. Bioorg Med Chem Lett 27:620-625
Liu, Jun-Yan; Morisseau, Christophe; Huang, Huazhang et al. (2016) Screening of soluble epoxide hydrolase inhibitory ingredients from traditional Chinese medicines for anti-inflammatory use. J Ethnopharmacol 194:475-482
Imig, J D (2016) Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function. Adv Pharmacol 77:105-41
Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan et al. (2015) Biological evaluation of a novel sorafenib analogue, t-CUPM. Cancer Chemother Pharmacol 75:161-71
Walkowska, A; Kuczeriszka, M; Sadowski, J et al. (2015) High salt intake increases blood pressure in normal rats: putative role of 20-HETE and no evidence on changes in renal vascular reactivity. Kidney Blood Press Res 40:323-34
Liu, Jun-Yan; Tsai, Hsing-Ju; Morisseau, Christophe et al. (2015) In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors. Biochem Pharmacol 98:718-31
Sporková, Alexandra; Jíchová, Sárka; Husková, Zuzana et al. (2014) Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: studies in Cyp1a1-Ren-2 transgenic rats. Clin Exp Pharmacol Physiol 41:1003-13
Mohamed, Islam N; Hafez, Sherif S; Fairaq, Arwa et al. (2014) Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia 57:413-23
Bettaieb, Ahmed; Chahed, Samah; Tabet, George et al. (2014) Effects of soluble epoxide hydrolase deficiency on acute pancreatitis in mice. PLoS One 9:e113019

Showing the most recent 10 out of 93 publications