Parallel improvement of sodium and chloride transport defects by miglustat (n-butyldeoxynojyrimicin) in cystic fibrosis epithelial cells.J Pharmacol Exp Ther 2008; 325(3):1016-23JP
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 hall-mark 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 degrees 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 cftr(F508del/F508del) mice, like with CF15 cells, we found normalization of amiloride-sensitive Isc. Moreover, oral administration of miglustat (6 days) decreased the amiloride-sensitive Isc in cftr(F508del/F508del) mice 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.