CYP2J2-produced epoxyeicosatrienoic acids attenuate ischemia/reperfusion-induced acute kidney injury by activating the SIRT1-FoxO3a pathway

Abstract Cytochrome P450 (CYP) epoxygenases can metabolize arachidonic acids to epoxyeicosatrienoic acids (EETs), which play a protective role in the renal system, but their involvement in ischemia/reperfusion (I/R)-induced acute kidney injury remains unknown. Here, using a rat model, we demonstrated that forced CYP2J2 expression attenuated I/R-induced renal dysfunction and protected histological integrity. We showed that CYP2J2 significantly decreased I/R-induced upregulation of blood urea nitrogen and serum creatinine and enhanced autophagy during I/R treatment. In addition, we determined the protective effect of CYP2J2 against I/R-caused apoptosis. We demonstrated that CYP2J2 overexpression attenuated the downregulation of SIRT1 and FoxO3a by I/R-induced injury. Moreover, exogenous 11,12-EET addition obviously promoted I/R-induced autophagic flux and suppressed I/R-induced apoptosis through SIRT1–FoxO3a signaling activation. Our data indicate that CYP2J2-produced EETs improve I/R-caused kidney injury by activating the SIRT1–FoxO3a signaling pathway, which protects from renal I/R injury.