Tags

Type your tag names separated by a space and hit enter

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

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+Show Affiliations

Institut de Physiologie et Biologie Cellulaires, Centre National de la Recherche Scientifique, Université de Poitiers, 86022 Poitiers, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18309088

Citation

Noël, Sabrina, et al. "Parallel Improvement of Sodium and Chloride Transport Defects By Miglustat (n-butyldeoxynojyrimicin) in Cystic Fibrosis Epithelial Cells." The Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 3, 2008, pp. 1016-23.
Noël S, Wilke M, Bot AG, et al. Parallel improvement of sodium and chloride transport defects by miglustat (n-butyldeoxynojyrimicin) in cystic fibrosis epithelial cells. J Pharmacol Exp Ther. 2008;325(3):1016-23.
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), pp. 1016-23. doi:10.1124/jpet.107.135582.
Noël S, et al. Parallel Improvement of Sodium and Chloride Transport Defects By Miglustat (n-butyldeoxynojyrimicin) in Cystic Fibrosis Epithelial Cells. J Pharmacol Exp Ther. 2008;325(3):1016-23. PubMed PMID: 18309088.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parallel improvement of sodium and chloride transport defects by miglustat (n-butyldeoxynojyrimicin) in cystic fibrosis epithelial cells. AU - Noël,Sabrina, AU - Wilke,Martina, AU - Bot,Alice G M, AU - De Jonge,Hugo R, AU - Becq,Frédéric, Y1 - 2008/02/28/ PY - 2008/3/1/pubmed PY - 2008/6/17/medline PY - 2008/3/1/entrez SP - 1016 EP - 23 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 325 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18309088/Parallel_improvement_of_sodium_and_chloride_transport_defects_by_miglustat__n_butyldeoxynojyrimicin__in_cystic_fibrosis_epithelial_cells_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18309088 DB - PRIME DP - Unbound Medicine ER -