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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 294/4/L654    most recent 00430.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miller, T. J. Articles by Davis, P. B. Search for Related Content PubMed PubMed Citation Articles by Miller, T. J. Articles by Davis, P. B.

FXYD5 modulates Na⁺ absorption and is increased in cystic fibrosis airway epithelia

Departments of ¹Pharmacology and ²Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio

Submitted 17 October 2007 ; accepted in final form 3 February 2008

FXYD5, also known as dysadherin, belongs to a family of tissue-specific regulators of the Na⁺-K⁺-ATPase. We determined the kinetic effects of FXYD5 on Na⁺-K⁺-ATPase pump activity in stably transfected Madin-Darby canine kidney cells. FXYD5 significantly increased the apparent affinity for Na⁺ twofold and decreased the apparent affinity for K⁺ by 60% with a twofold increase in V_max of K⁺, a pattern that would increase activity and Na⁺ removal from the cell. To test the effect of increased Na⁺ uptake on FXYD5 expression, we analyzed Madin-Darby canine kidney cells stably transfected with an inducible vector expressing all three subunits of the epithelial Na⁺ channel (ENaC). Na⁺-K⁺-ATPase activity increased sixfold after 48-h ENaC induction, but FXYD5 expression decreased 75%. FXYD5 expression was also decreased in lung epithelia from mice that overexpress ENaC, suggesting that chronic Na⁺ absorption by itself downregulates epithelial FXYD5 expression. Patients with cystic fibrosis (CF) display ENaC-mediated hyperabsorption of Na⁺ in the airways, accompanied by increased Na⁺-K⁺-ATPase activity. However, FXYD5 was significantly increased in the lungs and nasal epithelium of CF mice as assessed by RT-PCR, immunohistochemistry, and immunoblot analysis (P < 0.001). FXYD5 was also upregulated in nasal scrapings from human CF patients compared with controls (P < 0.02). Treatment of human tracheal epithelial cells with a CFTR inhibitor (I-172) confirmed that loss of CFTR function correlated with increased FXYD5 expression (P < 0.001), which was abrogated by an inhibitor of NF-B. Thus FXYD5 is upregulated in CF epithelia, and this change may exacerbate the Na⁺ hyperabsorption and surface liquid dehydration observed in CF airway epithelia.

Na⁺-K⁺-ATPase; sodium transport