Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension. Am J Physiol Renal Physiol 2009 Sep;297(3):F740-8
Date
06/26/2009Pubmed ID
19553349Pubmed Central ID
PMC2739707DOI
10.1152/ajprenal.00098.2009Scopus ID
2-s2.0-69449093425 (requires institutional sign-in at Scopus site) 124 CitationsAbstract
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 microg/day) compared with control (17 +/- 1 microg/day) and was blunted in the Ephx2-/- DOCA-salt mice (97 +/- 23 microg/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.
Author List
Manhiani M, Quigley JE, Knight SF, Tasoobshirazi S, Moore T, Brands MW, Hammock BD, Imig JDMESH terms used to index this publication - Major topics in bold
AlbuminuriaAnimals
Benzoates
Blood Pressure
Chemokine CCL2
Desoxycorticosterone
Disease Models, Animal
Enzyme Inhibitors
Epoxide Hydrolases
Gene Deletion
Hypertension
Kidney Glomerulus
Macrophages
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Nephritis
Protein Structure, Tertiary
Sodium Chloride, Dietary
Time Factors
Urea
