Document Detail

Ouabain binds with high affinity to the Na,K-ATPase in human polycystic kidney cells and induces extracellular signal-regulated kinase activation and cell proliferation.
MedLine Citation:
PMID:  17151336     Owner:  NLM     Status:  MEDLINE    
In autosomal dominant polycystic kidney disease (ADPKD), cyst formation and enlargement require proliferation of mural renal epithelial cells and the transepithelial secretion of fluid into the cyst cavity. Na,K-ATPase is essential for solute and water transport in ADPKD cells, and ouabain blocks fluid secretion in these cells. By binding to the Na,K-ATPase, ouabain also induces proliferation in some cell types. Surprisingly, it was found that nanomolar concentrations of ouabain, similar to those circulating in blood, induced ADPKD cell proliferation but had no statistically significant effect on normal human kidney (NHK) cells. Ouabain, acting from the basolateral side of the cells, also caused an increase in the level of phosphorylated extracellular signal-regulated kinases (ERK). Mitogen-activated protein kinase kinase (MEK) inhibitor U0126 blocked ouabain-induced ERK activation and cell proliferation, suggesting that ouabain effect is mediated through the MEK-ERK pathway. In contrast to NHK cells, the dose-response curve for ouabain inhibition of Na,K-ATPase activity indicated that approximately 20% of the enzyme in ADPKD cells exhibits a higher affinity for ouabain. The increased ouabain affinity of ADPKD cells was not due to differences in Na,K-ATPase isoform expression because these cells, like NHK cells, possess only the alpha1 and beta1 subunits. The gamma variants of the Na,K-ATPase also are expressed in the cells but are elevated in ADPKD cells. Currently, the basis for the differences in ouabain sensitivity of NHK and ADPKD cells is unknown. It is concluded that ouabain stimulates proliferation in ADPKD cells by binding to the Na,K-ATPase with high affinity and via activation of the MEK-ERK pathway.
Anh-Nguyet T Nguyen; Darren P Wallace; Gustavo Blanco
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-12-06
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  18     ISSN:  1046-6673     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-01     Completed Date:  2007-03-14     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  46-57     Citation Subset:  IM    
Department of Molecular and Integrative Physiology, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
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MeSH Terms
Base Sequence
Cell Proliferation / drug effects
Cells, Cultured
DNA Primers / genetics
Enzyme Inhibitors / metabolism,  pharmacology
Epithelial Cells / drug effects,  metabolism,  pathology
Isoenzymes / antagonists & inhibitors,  genetics,  metabolism
Kidney / cytology,  drug effects,  metabolism
MAP Kinase Signaling System / drug effects
Ouabain / metabolism*,  pharmacology
Polycystic Kidney, Autosomal Dominant / genetics,  metabolism*,  pathology
RNA, Messenger / genetics,  metabolism
Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors,  genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/DNA Primers; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/RNA, Messenger; 630-60-4/Ouabain; EC ATPase

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