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Ketamine Increases Permeability and Alters Epithelial Phenotype of Renal Distal Tubular Cells via a GSK‐3β‐Dependent Mechanism
Author(s) -
Shyu HsinYi,
Ko ChunJung,
Luo YuChen,
Lin HsinYing,
Wu ShangRu,
Lan ShaoWei,
Cheng TaiShan,
Hu ShihHsiung,
Lee MingShyue
Publication year - 2016
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25372
Subject(s) - downregulation and upregulation , pi3k/akt/mtor pathway , occludin , protein kinase b , chemistry , microbiology and biotechnology , ly294002 , paracellular transport , motility , osteopontin , cancer research , tight junction , phosphorylation , biology , signal transduction , endocrinology , permeability (electromagnetism) , biochemistry , membrane , gene
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. J. Cell. Biochem. 117: 881–893, 2016. © 2015 Wiley Periodicals, Inc.