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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/F740    most recent 00098.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by Manhiani, M. Articles by Imig, J. D. PubMed PubMed Citation Articles by Manhiani, M. Articles by Imig, J. D.

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

¹Vascular Biology Center and ²Department of Physiology, Medical College of Georgia, Augusta, Georgia; ³Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin; and ⁴Department of Entomology and UCD Cancer Research Center, University of California, Davis, California

Submitted 18 February 2009 ; accepted in final form 22 June 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 µg/day) compared with 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 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.

deoxycorticosterone acetate; blood pressure; Ephx2; high salt; albuminuria; NF-B; glomerular injury