Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury

Ahmed Bettaieb, Shinichiro Koike, Samah Chahed, Yi Zhao, Santana Bachaalany, Nader Hashoush, James Graham, Huma Fatima, Peter J Havel, Artiom Gruzdev, Darryl C. Zeldin, Bruce D. Hammock, Fawaz Haj

Research output: Contribution to journalEditorial

13 Scopus citations

Abstract

Podocytes play an important role in maintaining glomerular function, and podocyte injury is a significant component in the pathogenesis of proteinuria. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose genetic deficiency and pharmacological inhibition have beneficial effects on renal function, but its role in podocytes remains unexplored. The objective of this study was to investigate the contribution of sEH in podocytes to lipopolysaccharide (LPS)-induced kidney injury. We report increased sEH transcript and protein expression in murine podocytes upon LPS challenge. To determine the function of sEH in podocytes in vivo we generated podocyte-specific sEH-deficient (pod-sEHKO) mice. Following LPS challenge, podocyte sEH-deficient mice exhibited lower kidney injury, proteinuria, and blood urea nitrogen concentrations than controls suggestive of preserved renal function. Also, renal mRNA and serum concentrations of inflammatory cytokines IL-6, IL-1β, and TNFα were significantly lower in LPS-treated pod-sEHKO than control mice. Moreover, podocyte sEH deficiency was associated with decreased LPS-induced NF-κB and MAPK activation and attenuated endoplasmic reticulum stress. Furthermore, the protective effects of podocyte sEH deficiency in vivo were recapitulated in E11 murine podocytes treated with a selective sEH pharmacological inhibitor. Altogether, these findings identify sEH in podocytes as a contributor to signaling events in acute renal injury and suggest that sEH inhibition may be of therapeutic value in proteinuria. Enzymes: Soluble epoxide hydrolase: EC 3.3.2.10.

Original languageEnglish (US)
Pages (from-to)1970-1986
Number of pages17
JournalFEBS Journal
Volume284
Issue number13
DOIs
StatePublished - Jul 1 2017

Keywords

  • knockout mice
  • podocyte
  • proteinuria
  • soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Bettaieb, A., Koike, S., Chahed, S., Zhao, Y., Bachaalany, S., Hashoush, N., Graham, J., Fatima, H., Havel, P. J., Gruzdev, A., Zeldin, D. C., Hammock, B. D., & Haj, F. (2017). Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury. FEBS Journal, 284(13), 1970-1986. https://doi.org/10.1111/febs.14100