Cytochrome P450 epoxygenase CYP2J2 attenuates nephropathy in streptozotocin-induced diabetic mice

Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play important and diverse roles in the cardiovascular system. The anti-inflammatory, anti-apoptotic, pro-angiogenic, and anti-hypertensive properties of EETs in the cardiovascular system suggest a beneficial role for EETs in diabetic nephropathy. This study investigated the effects of endothelial specific overexpression of CYP2J2 epoxygenase on diabetic nephropathy in streptozotocin-induced diabetic mice. Endothelial CYP2J2 overexpression attenuated renal damage as measured by urinary microalbumin and glomerulosclerosis. These effects were associated with inhibition of TGF-β/Smad signaling in the kidney. Indeed, overexpression of CYP2J2 prevented TGF-β1-induced renal tubular epithelial–mesenchymal transition in vitro. These findings highlight the beneficial roles of the CYP epoxygenase–EET system in the pathogenesis of diabetic nephropathy.

► This study is the first report about the protection role of CYP2J2 in diabetic nephropathy in vivo. ► Endothelial overexpression of CYP2J2 attenuates activation of the TGF-β/Smad signaling pathway in diabetic kidney mice. ► EETs attenuate TGF-β1-induced tubular epithelial–mesenchymal transdifferentiation on HK-2 cells. ► EETs attenuate the effects of TGF-β1 through a mechanism that involves activation of EGFR and PPARγ.