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CELLULAR AND MOLECULAR

Parallel Improvement of Sodium and Chloride Transport Defects by Miglustat (n-Butyldeoxynojyrimicin) in Cystic Fibrosis Epithelial Cells

Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, Centre National de la Recherche Scientifique, Poitiers, France (S.N., F.B.); and Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands (M.W., A.G.M.B., H.R.D.J.).

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°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.

Address correspondence to: Dr. Frédéric Becq, Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6187, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers, France. E-mail: frederic.becq{at}univ-poitiers.fr

This article has been cited by other articles:

				B. Lubamba, J. Lebacq, P. Lebecque, R. Vanbever, A. Leonard, P. Wallemacq, and T. Leal Airway Delivery of Low-Dose Miglustat Normalizes Nasal Potential Difference in F508del Cystic Fibrosis Mice Am. J. Respir. Crit. Care Med., June 1, 2009; 179(11): 1022 - 1028. [Abstract] [Full Text] [PDF]