Author:
Miller Timothy J.,Davis Pamela B.
Abstract
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 Vmaxof 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-κB. Thus FXYD5 is upregulated in CF epithelia, and this change may exacerbate the Na+hyperabsorption and surface liquid dehydration observed in CF airway epithelia.
Publisher
American Physiological Society
Subject
Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology
Cited by
22 articles.
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