Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling

Bing Qing Deng, Ying Luo, Xin Kang, Chang Bin Li, Christophe Morisseau, Jun Yang, Kin Sing Stephen Lee, Jian Huang, Da Yong Hu, Ming Yu Wu, Ai Peng, Bruce D. Hammock, Jun Yan Liu

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15)-epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/ reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3β (GSK3β) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3β phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3β phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3β phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.

Original languageEnglish (US)
Pages (from-to)12608-12613
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number47
DOIs
StatePublished - Nov 21 2017

Keywords

  • Epoxydocosapentaenoic acid
  • Epoxyeicosatrienoic acid
  • GSK3β phosphorylation
  • Renal tubular epithelial cells
  • siRNA

ASJC Scopus subject areas

  • General

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    Deng, B. Q., Luo, Y., Kang, X., Li, C. B., Morisseau, C., Yang, J., Lee, K. S. S., Huang, J., Hu, D. Y., Wu, M. Y., Peng, A., Hammock, B. D., & Liu, J. Y. (2017). Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling. Proceedings of the National Academy of Sciences of the United States of America, 114(47), 12608-12613. https://doi.org/10.1073/pnas.1705615114