title: Soluble epoxide hydrolase inhibition ameliorates proteinuria-induced epithelial-mesenchymal transition by regulating the PI3K-Akt-GSK-3β signaling pathway.
abstract: Soluble epoxide hydrolase (sEH) plays an essential role in chronic kidney disease by hydrolyzing renoprotective 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 (α-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-3β (GSK-3β). The PI3K inhibitor LY-294002 inhibited phosphorylation of Akt and GSK-3β 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-3β phosphorylation. EMT associated E-cadherin suppression, α-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-3β 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-3β signaling pathway. Targeting sEH might be a potential strategy for the treatment of EMT and renal fibrosis.
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Yaoxian
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Jing
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Zhengqian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Beijing 100191, China. Electronic address: bjwangyue@sina.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007850:Lauric Acids / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D002867:Chromones; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D004851:Epoxide Hydrolases; D000218:Adamantane
keywords: Adriamycin-induced nephropathy; Epithelial-mesenchymal transition; Proteinuria; Soluble epoxide hydrolase