https://scholars.lib.ntu.edu.tw/handle/123456789/454724
標題: | Ketamine Increases Permeability and Alters Epithelial Phenotype of Renal Distal Tubular Cells via a GSK-3β-Dependent Mechanism | 作者: | Shyu H.-Y. Chun-Jung Ko Luo Y.-C. Lin H.-Y. Wu S.-R. Lan S.-W. Cheng T.-S. Hu S.-H. MING-SHYUE LEE |
公開日期: | 2016 | 出版社: | Wiley-Liss Inc. | 卷: | 117 | 期: | 4 | 起(迄)頁: | 881-893 | 來源出版物: | Journal of Cellular Biochemistry | 摘要: | Ketamine, a dissociative anesthetic, is misused and abused worldwide as an illegal recreational drug. In addition to its neuropathic toxicity, ketamine abuse has numerous effects, including renal failure; however, the underlying mechanism is poorly understood. The process called epithelial phenotypic changes (EPCs) causes the loss of cell-cell adhesion and cell polarity in renal diseases, as well as the acquisition of migratory and invasive properties. Madin-Darby canine kidney cells, an in vitro cell model, were subjected to experimental manipulation to investigate whether ketamine could promote EPCs. Our data showed that ketamine dramatically decreased transepithelial electrical resistance and increased paracellular permeability and junction disruption, which were coupled to decreased levels of apical junctional proteins (ZO-1, occludin, and E-cadherin). Consistent with the downregulation of epithelial markers, the mesenchymal markers N-cadherin, fibronectin, and vimentin were markedly upregulated following ketamine stimulation. Of the E-cadherin repressor complexes tested, the mRNA levels of Snail, Slug, Twist, and ZEB1 were elevated. Moreover, ketamine significantly enhanced migration and invasion. Ketamine-mediated changes were at least partly caused by the inhibition of GSK-3β activity through Ser-9 phosphorylation by the PI3K/Akt pathway. Inhibiting PI3K/Akt with LY294002 reactivated GSK-3β and suppressed ketamine-enhanced permeability, EPCs, and motility. These findings were recapitulated by the inactivation of GSK-3β using the inhibitor 3F8. Taken together, these results provide evidence that ketamine induces renal distal tubular EPCs through the downregulation of several junction proteins, the upregulation of mesenchymal markers, the activation of Akt, and the inactivation of GSK-3β. ? 2015 Wiley Periodicals, Inc. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84958191651&doi=10.1002%2fjcb.25372&partnerID=40&md5=5ffca298000413a8d8e22ba0d2fceb00 https://scholars.lib.ntu.edu.tw/handle/123456789/454724 |
ISSN: | 0730-2312 | DOI: | 10.1002/jcb.25372 | SDG/關鍵字: | fibronectin; glycogen synthase kinase 3beta; ketamine; messenger RNA; nerve cell adhesion molecule; occludin; phosphatidylinositol 3 kinase; protein kinase B; serine; transcription factor Slug; transcription factor Snail; transcription factor Twist; transcription factor ZEB1; vimentin; analgesic agent; cadherin; fibronectin; glycogen synthase kinase 3; glycogen synthase kinase 3beta; ketamine; occludin; protein ZO1; transcription factor; transcription factor Snail; Twist related protein 1; vimentin; zinc finger protein; animal cell; Article; cell adhesion; cell membrane permeability; cell migration; cell polarity; concentration (parameters); controlled study; down regulation; electric resistance; enzyme inactivation; enzyme inhibition; epithelium; in vitro study; kidney tubule cell; MDCK cell line; molecular mechanics; nonhuman; phenotype; priority journal; protein phosphorylation; tight junction; tumor invasion; upregulation; animal; antagonists and inhibitors; cell junction; cell membrane; cell membrane permeability; cell motion; dog; drug effects; epithelial mesenchymal transition; gene expression regulation; genetics; metabolism; phenotype; signal transduction; Analgesics; Animals; Cadherins; Cell Adhesion; Cell Membrane; Cell Membrane Permeability; Cell Movement; Cell Polarity; Dogs; Epithelial-Mesenchymal Transition; Fibronectins; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Intercellular Junctions; Ketamine; Madin Darby Canine Kidney Cells; Occludin; Phenotype; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Twist-Related Protein 1; Vimentin; Zinc Fingers; Zonula Occludens-1 Protein |
顯示於: | 生物化學暨分子生物學科研究所 |
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