Abstract
Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Inhibition of soluble epoxide hydrolase (sEH) has been reported previously to attenuate the kidney injury in cisplatin‐caused AKI. However, the effect of sEH inhibition on ischemia/reperfusion (I/R)‐caused‐AKI remains unknown. In addition, the mechanism underlying the benefit of sEH inhibition to AKI has not been well understood. Here we report that epoxyeicosatrienoic acids (EETs) are the major mediators responsible for the beneficial effect of sEH inhibition in I/R‐caused AKI. Inhibition of sEH resulted in a significant increase in plasma level of 14(15)‐EET. Administration of both 14(15)‐EET alone and TPPU (a potent sEH inhibitor) significantly prolonged the survival of AKI mice. Co‐administration of 14(15)‐EET with TPPU enhanced such effect in survival. Administration of 14(15)‐EET with or without TPPU to AKI mice significantly attenuated the kidney injury, which was supported by the histological analysis of renal tissue, plasma levels of creatinine and urea nitrogen, and renal levels of NGAL. Furthermore, 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. Therefore, inhibition of sEH attenuates kidney injury via, at least partially, 14(15)‐EET modulating the apoptosis of RTECs and GSK3β phosphorylation in mRTECs. This study provides AKI patients with promising therapeutic strategies.Support or Funding InformationThis study was supported in part by NSFC grants 81470588 and 81100090, as well as NIEHS Grant (R01 ES02710), NIEHS Superfund Grant (P42 ES04699), NIH/NHLBI grant (R01 HL59699‐06A1), and a Translational Technology Grant from the UC Davis Medical Center. K.S.S.L. is supported by NIEHS Grant R00 ES024806.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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