Document Detail

Hypotonic stress upregulates β- and γ-ENaC expression through suppression of ERK by inducing MKP-1.
MedLine Citation:
PMID:  22573375     Owner:  NLM     Status:  MEDLINE    
We investigated a physiological role for ERK, a member of the MAPK family, in the hypotonic stimulation of epithelial Na(+) channel (ENaC)-mediated Na(+) reabsorption in renal epithelial A6 cells. We show that hypotonic stress causes a major dephosphorylation of ERK following a rapid transient phosphorylation. PD98059 (a MEK inhibitor) increases dephosphorylated ERK and enhances the hypotonic-stress-stimulated Na(+) reabsorption. ERK dephosphorylation is mediated by MAPK phosphatase (MKP). Hypotonic stress activates p38, which in turn induces MKP-1 and to a lesser extent MKP-3 mRNA expression. Inhibition of p38 suppresses MKP-1 induction, preventing hypotonic stress from dephosphorylating ERK. Inhibition of MKP-1 and -3 by the inhibitor NSC95397 also suppresses the hypotonicity-induced dephosphorylation of ERK. NSC95397 reduces both β- and γ-ENaC mRNA expression and ENaC-mediated Na(+) reabsorption stimulated by hypotonic stress. In contrast, pretreatment with PD98059 significantly enhances mRNA and protein expression of β- and γ-ENaC even under isotonic conditions. However, PD98059 only stimulates Na(+) reabsorption in response to hypotonic stress, suggesting that ERK inactivation by itself (i.e., under isotonic conditions) is not sufficient to stimulate Na(+) reabsorption, even though ERK inactivation enhances β- and γ-ENaC expression. Based on these results, we conclude that hypotonic stress stimulates Na(+) reabsorption through at least two signaling pathways: 1) induction of MKP-1 that suppresses ERK activity and induces β- and γ-ENaC expression, and 2) promotion of translocation of the newly synthesized ENaC to the apical membrane.
Naomi Niisato; Mariko Ohta; Douglas C Eaton; Yoshinori Marunaka
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-09
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  303     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-16     Completed Date:  2012-10-02     Revised Date:  2013-07-17    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F240-52     Citation Subset:  IM    
Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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MeSH Terms
Cells, Cultured
Dual Specificity Phosphatase 1 / metabolism*
Dual Specificity Phosphatase 6 / metabolism
Enzyme Inhibitors / pharmacology
Epithelial Cells / drug effects*,  metabolism
Epithelial Sodium Channels / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism*
Flavonoids / pharmacology
Hypotonic Solutions / pharmacology*
Kidney / cytology,  metabolism*
MAP Kinase Kinase 4 / metabolism
Models, Animal
Naphthoquinones / pharmacology
Signal Transduction / drug effects
Up-Regulation / drug effects*
Xenopus laevis
p38 Mitogen-Activated Protein Kinases / metabolism
Grant Support
Reg. No./Substance:
0/2,3-bis(2-hydroxyethylsulfanyl)-(1,4)naphthoquinone; 0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Enzyme Inhibitors; 0/Epithelial Sodium Channels; 0/Flavonoids; 0/Hypotonic Solutions; 0/Naphthoquinones; EC Signal-Regulated MAP Kinases; EC Mitogen-Activated Protein Kinases; EC Kinase Kinase 4; EC Specificity Phosphatase 1; EC Specificity Phosphatase 6

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

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