Cystic fibrosis, an autosomal recessive disease frequently diagnosed in the Caucasian population, is characterized by deficient Cl-transport due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A second major hallmark of the disease is Na+hyperabsorption by the airways, mediated by the epithelial Na+channel (ENaC). In this study, we report that in human airway epithelial CF15 cells treated with the CFTR corrector miglustat (n-butyldeoxynojyrimicin), whole-cell patch-clamp experiments showed reduced amiloride-sensitive ENaC current in parallel with a rescue of defective CFTR Cl-channel activity activated by forskolin and genistein. Similar results were obtained with cells maintained in culture at 27°C for 24 h before electrophysiology experiments. With monolayers of polarized CF15 cells, short-circuit current (Isc) measurements also show normalization of Na+and Cl-currents. In excised nasal epithelium of cftrF508del/F508delmice, like with CF15 cells, we found normalization of amiloride-sensitive Isc. Moreover, oral administration of miglustat (6 days) decreased the amiloride-sensitive Isc in cftrF508del/F508delmice but had no effect on cftr-/-mice. Our results thus show that rescuing the trafficking-deficient F508del-CFTR by miglustat down-regulates Na+absorption. A miglustat-based treatment of CF patients may thus have a beneficial effect both on Cl-and Na+transports. Copyright

dx.doi.org/10.1124/jpet.107.135582, hdl.handle.net/1765/28946
The Journal of Pharmacology and Experimental Therapeutics
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Erasmus MC: University Medical Center Rotterdam

Noël, S, Wilke, M, Bot, A.G, de Jonge, H.R, & Becq, F. (2008). Parallel improvement of sodium and chloride transport defects by miglustat (n-butyldeoxynojyrimicin) in cystic fibrosis epithelial cells. The Journal of Pharmacology and Experimental Therapeutics, 325(3), 1016–1023. doi:10.1124/jpet.107.135582