Submitted on February 19, 2009
Revised on June 7, 2009
Accepted on June 22, 2009
Soluble Epoxide Hydrolase Gene Deletion Attenuates Renal Injury and Inflammation with DOCA-salt Hypertension
Marlina Manhiani, Jeffrey E. Quigley, Sarah F. Knight, Shiva Tasoobshirazi, TarRhonda Moore, Michael W. Brands1, Bruce D Hammock2, and John D. Imig3*
1 Medical College of Georgia
2 University of California, Davis
3 Medical College of Wisconsin
* To whom correspondence should be addressed. E-mail: jdimig{at}mcw.edu.
Inhibition of soluble epoxide hydrolase (sEH) has been shown to be renal protective in rat models of salt sensitive hypertension. Here, we hypothesize that targeted disruption of the sEH gene (Ephx2) prevents both renal inflammation and injury in deoxycorticosterone acetate plus high salt (DOCA-salt) hypertensive mice. Mean arterial blood pressure (MAP) increased significantly in the DOCA-salt groups and MAP was lower in Ephx2-/- DOCA-salt (129 ± 3 mmHg) compared to wild type (WT) DOCA-salt (145 ± 2 mmHg) mice. Following 21 days of treatment, WT DOCA-salt urinary MCP-1 excretion increased from control and was attenuated in the Ephx2-/-DOCA-salt group. Macrophage infiltration was reduced in Ephx2-/- DOCA-salt compared to WT DOCA-salt mice. Albuminuria increased in WT DOCA-salt (278 ± 55 µg/day) compared to control (17 ± 1 µg/day) and was blunted in the Ephx2-/- DOCA-salt mice (97 ± 23 µg/day). Glomerular nephrin expression demonstrated an inverse relationship with albuminuria. Nephrin immunofluorescence was greater in the Ephx2-/- DOCA-salt group (3.4± 0.3 RFU) compared to WT DOCA-salt group (1.1 ± 0.07 RFU). Reduction in renal inflammation and injury was also seen in WT DOCA-salt mice treated with a sEH inhibitor (tAUCB, trans-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid), demonstrating that the C-terminal hydrolase domain of sEH enzyme is responsible for renal protection with DOCA-salt hypertension. These data demonstrate that Ephx2 gene deletion decreases blood pressure, attenuates renal inflammation, and ameliorates glomerular injury in DOCA-salt hypertension.
