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

  1. Jun-Yan Liua,1
  1. aCenter for Nephrology and Metabolomics and Division of Nephrology and Rheumatology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 210072, People’s Republic of China;
  2. bDepartment of Entomology and Nematology, University of California, Davis, CA 95616;
  3. cComprehensive Cancer Center, University of California, Davis, CA 95616
  1. Contributed by Bruce D. Hammock, October 12, 2017 (sent for review April 12, 2017; reviewed by Deanna L. Kroetz and Alan Parrish)


This study demonstrates that 19 (20)-EDP, the major epoxide metabolite of ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid, aggravates while 14 (15)-EET, the major epoxide metabolite of ω-6 PUFA arachidonic acid, alleviates acute kidney injury (AKI) in a murine model. The metabolite 19 (20)-EDP significantly shortened while 14 (15)-EET significantly prolonged the survival of AKI mice. Opposite effects of the EDP and EET regioisomers in ischemia/reperfusion-caused kidney injury may partially account for the opposite effects of 14 (15)-EET and 19 (20)-EDP in modulation of the hypoxia/reoxygenation-caused apoptosis of renal tubular epithelial cells and the phosphorylation of GSK3β, a promising therapeutic target for AKI. However, our study provides a caution regarding the use of dietary ω-3 fatty acids in renal injury.


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.


  • ?1To whom correspondence may be addressed. Email: bdhammock{at}ucdavis.edu or jyliu{at}tongji.edu.cn.
  • Author contributions: B.D.H. and J.-Y.L. designed research; B.-Q.D., Y.L., X.K., C.-B.L., C.M., J.Y., J.H., D.-Y.H., M.-Y.W., A.P., and J.-Y.L. performed research; K.S.S.L. and B.D.H. contributed new reagents/analytic tools; B.-Q.D., Y.L., X.K., C.M., J.Y., and J.-Y.L. analyzed data; and B.D.H. and J.-Y.L. wrote the paper.

  • Reviewers: D.L.K., University of California, San Francisco; and A.P., University of Missouri.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1705615114/-/DCSupplemental.

Published under the PNAS license.

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