Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension.
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.
Manhiani
Marlina
M
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA.
Quigley
Jeffrey E
JE
Knight
Sarah F
SF
Tasoobshirazi
Shiva
S
Moore
TarRhonda
T
Brands
Michael W
MW
Hammock
Bruce D
BD
Imig
John D
JD
D000419:Albuminuria / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure; D018932:Chemokine CCL2 / Q000652:urine; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D006973:Hypertension / Q000150:complications* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009393:Nephritis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017434:Protein Structure, Tertiary; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D017673:Sodium Chloride, Dietary; C113267:nephrin; D003900:Desoxycorticosterone; D014508:Urea; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse