title: Parallel improvement of sodium and chloride transport defects by miglustat (n-butyldeoxynojyrimicin) in cystic fibrosis epithelial cells.
abstract: 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.
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique, Université de Poitiers, 86022 Poitiers, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Noël
authors.forename: Martina
authors.initials: M
authors.lastname: Wilke
authors.forename: Alice G M
authors.initials: AG
authors.lastname: Bot
authors.forename: Hugo R
authors.initials: HR
authors.lastname: De Jonge
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002712:Chlorides / Q000502:physiology; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000187:drug effects* / Q000502:physiology; D012964:Sodium / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D002712:Chlorides; D026941:Sodium Channel Blockers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017485:1-Deoxynojirimycin; D000584:Amiloride; D012964:Sodium; C059896:miglustat