Document Detail

[Na+]i/[K+]i -independent death of ouabain-treated renal epithelial cells is not mediated by Na+,K+ -ATPase internalization and de novo gene expression.
MedLine Citation:
PMID:  17622553     Owner:  NLM     Status:  MEDLINE    
The cytotoxic effect of long-term exposure of renal epithelial cells to ouabain and other cardiotonic steroids (CTS) is mediated by the interaction of these compounds with Na(+),K(+)-ATPase but is independent of the inhibition of Na(+),K(+)-ATPase-mediated ion fluxes. Sustained application of CTS also leads to Na(+),K(+)-ATPase endocytosis and its translocation into the nuclei that might trigger the cell death machinery via the regulation of gene expression. This study examines the role of Na(+),K(+)-ATPase internalization and de novo gene expression in the death of ouabain-treated C7-Madin-Darby canine kidney (MDCK) cells derived from distal tubules of the MDCK. In these cells, 6-h exposure to 3 microM ouabain led to the internalization of approximately 50% of plasmalemmal Na(+),K(+)-ATPase. Prolonged incubation in a K(+)-free medium abolished ouabain-induced Na(+),K(+)-ATPase internalization but did not affect the cytotoxic action of ouabain seen after 18-h incubation. Previously, it was shown that CTS-induced Na(+),K(+)-ATPase internalization is mediated by its interaction with Src within caveolae. Neither caveolae damage by cholesterol depletion with methyl-beta-cyclodextrin nor Src inhibition with 4-amino-5(4-chlorophenyl)-7-(t-butyl)pyrazol[3,4-d]pyridine affected the death of ouabain-treated C7-MDCK cells. Actinomycin D at the 0.1-microg/ml concentration almost completely abolished ribonucleic acid synthesis but did not protect C7-MDCK cells from the cytotoxic action of ouabain. Our results show that neither Na(+),K(+)-ATPase endocytosis nor de novo gene expression contributes to Na(+)(i), K(+)(i)-independent cell death signaling evoked by prolonged exposure to CTS.
Olga A Akimova; Pavel Hamet; Sergei N Orlov
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-07-11
Journal Detail:
Title:  Pflügers Archiv : European journal of physiology     Volume:  455     ISSN:  0031-6768     ISO Abbreviation:  Pflugers Arch.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2007-11-21     Completed Date:  2008-06-12     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0154720     Medline TA:  Pflugers Arch     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  711-9     Citation Subset:  IM    
Research Centre, Centre Hospitalier de l'Université de Montréal, Technôpole Angus, 2901 Rachel East, Montreal, Quebec H1W 4A4, Canada.
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MeSH Terms
Cardiotonic Agents / toxicity*
Caveolae / drug effects,  metabolism
Cell Death / drug effects
Cell Line
Cholesterol / deficiency
Dactinomycin / pharmacology
Endocytosis / drug effects
Enzyme Inhibitors / toxicity*
Epithelial Cells / drug effects*,  enzymology,  metabolism,  pathology
Gene Expression / drug effects
Kidney / drug effects*,  enzymology,  metabolism,  pathology
Nucleic Acid Synthesis Inhibitors / pharmacology
Ouabain / toxicity*
Potassium / metabolism
Protein Kinase Inhibitors / pharmacology
Pyrimidines / pharmacology
Sodium / metabolism
Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*,  metabolism
Time Factors
beta-Cyclodextrins / pharmacology
src-Family Kinases / antagonists & inhibitors,  metabolism
Reg. No./Substance:
0/AG 1879; 0/Cardiotonic Agents; 0/Enzyme Inhibitors; 0/Nucleic Acid Synthesis Inhibitors; 0/Protein Kinase Inhibitors; 0/Pyrimidines; 0/beta-Cyclodextrins; 0/methyl-beta-cyclodextrin; 50-76-0/Dactinomycin; 57-88-5/Cholesterol; 630-60-4/Ouabain; 7440-09-7/Potassium; 7440-23-5/Sodium; EC Kinases; EC ATPase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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