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'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells : modulation of the adherens junction complex by ketamine
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Hills, Claire E., Jin, Tianrong, Siamantouras, Eleftherios, Liu, Kuo-Kang, Jefferson, Kieran P. and Squires, Paul E. (2013) 'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells : modulation of the adherens junction complex by ketamine. PLoS One, Volume 8 (Number 8). Article number e71819. doi:10.1371/journal.pone.0071819 ISSN 1932-6203.
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Official URL: http://dx.doi.org/10.1371/journal.pone.0071819
Abstract
Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical
changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and b-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFb, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine R Medicine > RS Pharmacy and materia medica |
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Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
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Library of Congress Subject Headings (LCSH): | Ketamine, Ketamine abuse -- Great Britain, Drug abuse -- Great Britain, Renal tubular transport, Disorders of, Cell-mediated cytotoxicity | ||||
Journal or Publication Title: | PLoS One | ||||
Publisher: | Public Library of Science | ||||
ISSN: | 1932-6203 | ||||
Official Date: | 29 August 2013 | ||||
Dates: |
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Volume: | Volume 8 | ||||
Number: | Number 8 | ||||
Article Number: | Article number e71819 | ||||
DOI: | 10.1371/journal.pone.0071819 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Open Access (Creative Commons) | ||||
Date of first compliant deposit: | 25 December 2015 | ||||
Date of first compliant Open Access: | 25 December 2015 | ||||
Funder: | Teresa Rosenbaum Golden Charitable Trust, Diabetes UK | ||||
Grant number: | BDA: 12/0004546 (DUK) |
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