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. Brands, Bruce D. Hammock, John D. Imig

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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 μ/day) compared with control (17 ± 1 μay) and was blunted in the Ephx2-/- DOCA-salt mice (97 ± 23 μay). 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 2009

Keywords

  • Albuminuria
  • Blood pressure
  • Deoxycorticosterone acetate
  • Ephx2
  • Glomerular injury
  • High salt
  • NF-κB

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Manhiani, M., Quigley, J. E., Knight, S. F., Tasoobshirazi, S., Moore, T., Brands, M. W., Hammock, B. D., & Imig, J. D. (2009). Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension. American Journal of Physiology - Renal Physiology, 297(3). https://doi.org/10.1152/ajprenal.00098.2009