Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension

Manhiani M, Quigley JE, Knight SF, Tasoobshirazi S, Moore T, Brands MW, Hammock BD, Imig JD. Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension. Am J Physiol Renal Physiol 297: F740-F748, 2009. First published June 24, 2009; doi:10.1152/ajprenal.00098.2009. 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 with 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 with WT DOCA-salt mice. Albuminuria increased in WT DOCA-salt (278 +/- 55 mu g/day) compared with control (17 +/- 1 mu g/day) and was blunted in the Ephx2(-/-) DOCA-salt mice (97 +/- 23 mu g/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 with 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 {trans-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]-benzoic acid; tAUCB}, demonstrating that the C-terminal hydrolase domain of the 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.