title: Targeting ENaC as a Molecular Suspect in Cystic Fibrosis.
abstract: Cystic fibrosis (CF) is the most common life shortening autosomal inherited disorder, affecting 1 in 2500 newborns in the Caucasian population. In CF the lung pathology is associated with dehydration of the airways epithelial surface which in part results from Na(+) hyperabsorption via the epithelial sodium channel (ENaC). The molecular mechanisms of this Na(+) hyperabsorption and its correlation with the underlying genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) are not fully understood. However, it is obvious that a reduced Cl(-) secretion by CFTR and an enhanced Na+ absorption through ENaC lead to the so far incurable disease. Therefore, it could be indicated to pursue a double-tracked strategy in that way enabling Cl(-) secretion by a reconstitution of the defect CFTR as well as blocking ENaC to prevent Na(+) hyperabsorption. Since the cloning of CFTR great efforts have been done in delivery of CFTR for the correction of the reduced Cl(-) secretion. Positive benefits for the inhibition of the CF related Na(+) hyperabsorption offer technologies using small molecule inhibitors like ASOs or siRNA, which target translation and knockdown of ENaC, respectively. In this review we discuss possible CFTR/ENaC interactions in the context of CF, describe ENaC structure as well as some of the numerous attempts that were performed to prevent the Na(+) hyperabsorption in CF related lung disease. Thus, we give a short summary of e.g. amiloride therapy approaches and focus on inventive blocking efforts using ASOs and siRNA.
authors.affiliation: Institute of Animal Physiology, Westphalian Wilhelms-University Muenster, Schlossplatz 8, D-48143 Muenster, Germany. n.br@uni-muenster.de.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bangel-Ruland
authors.forename: Katja
authors.initials: K
authors.lastname: Tomczak
authors.forename: Wolf-Michael
authors.initials: WM
authors.lastname: Weber
mesh_terms: D000584:Amiloride / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics; D062686:Epithelial Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D053503:Epithelial Sodium Channels / Q000187:drug effects*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*; D012964:Sodium / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000584:Amiloride; D012964:Sodium