Soluble epoxide hydrolase inhibition ameliorates proteinuria-induced epithelial-mesenchymal transition by regulating the PI3K-Akt-GSK-3β signaling pathway

Soluble epoxide hydrolase (sEH) plays an essential role in chronic kidney disease by hydrolyzing reno-protective epoxyeicosatrienoic acids to the corresponding inactive dihydroxyeicosatrienoic acids. However, there have been few mechanistic studies elucidating the role of sEH in epithelial-mesenchymal transition (EMT). The present study investigated, in vitro and in vivo, the role of sEH in proteinuria-induced renal tubular EMT and the underlying signaling pathway. We report that urinary protein (UP) induced EMT in cultured NRK-52E cells, as evidenced by decreased E-cadherin expression, increased alpha-smooth muscle actin (alpha-SMA) expression, and the morphological conversion to a myofibroblast-like phenotype. UP incubation also resulted in upregulated sEH, activated phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling and increased phosphorylated glycogen synthase kinase-3 beta (GSK-3 beta). The PI3K inhibitor LY-294002 inhibited phosphorylation of Akt and GSK-3 beta as well as blocking EMT. Importantly, pharmacological inhibition of sEH with 12-(3-adamantan-1-yl- ureido)dodecanoic acid (AUDA) markedly suppressed PI3K-Akt activation and GSK-3 beta phosphorylation. EMT associated E-cadherin suppression, alpha-SMA elevation and phenotypic transition were also attenuated by AUDA. Furthermore, in rats with chronic proteinuric renal disease, AUDA treatment inhibited PI3K-Akt activation and GSK-3 beta phosphorylation, while attenuating levels of EMT markers. Overall, our findings suggest that sEH inhibition ameliorates proteinuria-induced renal tubular EMT by regulating the PI3K-Akt-GSK-3 beta signaling pathway. Targeting sEH might be a potential strategy for the treatment of EMT and renal fibrosis. (C) 2015 Elsevier Inc. All rights reserved.