title: Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis.
abstract: Cystic fibrosis (CF) is characterized by impaired Cl(-) secretion and increased Na(+) reabsorption in several tissues including respiratory epithelium. Many CFTR mutations have been identified over the past years. However, only a poor correlation between the genotype and lung phenotype was found suggesting additional factors influencing the phenotype and course of the disease. The serine/threonine kinase SGK1 has recently been shown to stimulate the activity of the epithelial Na(+) channel ENaC. A variety of stimuli such as aldosterone, cell shrinkage, insulin or TGF-beta1 stimulate transcription and activate the SGK1 kinase. Here we further examined the effects of SGK1 on ENaC and CFTR which have mutual interactions and we analyzed sgk1 mRNA abundance in lung tissue from CF patients. Coexpression of CFTR and h-SGK1 in Xenopus oocytes increased ENaC currents as previously described. In addition CFTR mediated currents were also stimulated. h-SGK1 accelerated the expression of the amiloride sensitive Na(+)- current in Xenopus oocytes paralleled by increased ENaC-protein abundance in the oocyte membrane, an effect which was reversed by a h-SGK1(K127R) mutation lacking the ATP-binding site. The cation selectivity or Na(+) affinity were not affected. However, coexpression of h-SGK1 with ENaC altered the sensitivity of the Na(+)-channel to the inhibitors amiloride and triamterene. The inhibitory effect of CFTR expression on ENaC current was not affected by coexpression of h-SGK1 in Xenopus oocytes. Lung tissue from CF patients strongly expressed the serine/threonine kinase h-sgk1 which was not the case for non-CF lung tissue. Loss of CFTR function itself in a CF lung epithelial cell line did not increase SGK1 expression. In summary, enhanced expression of h-SGK1 in epithelial cells of CF-lung tissue may be a novel pathophysiological factor contributing to increased Na(+) channel activity and thus to increased Na(+) transport in CF.
authors.affiliation: Dept. of Physiology I, University of Tübingen. wagnerca@hotmail.com
authors.forename: C A
authors.initials: CA
authors.lastname: Wagner
authors.forename: M
authors.initials: M
authors.lastname: Ott
authors.forename: K
authors.initials: K
authors.lastname: Klingel
authors.forename: S
authors.initials: S
authors.lastname: Beck
authors.forename: J
authors.initials: J
authors.lastname: Melzig
authors.forename: B
authors.initials: B
authors.lastname: Friedrich
authors.forename: K N
authors.initials: KN
authors.lastname: Wild
authors.forename: S
authors.initials: S
authors.lastname: Bröer
authors.forename: I
authors.initials: I
authors.lastname: Moschen
authors.forename: A
authors.initials: A
authors.lastname: Albers
authors.forename: S
authors.initials: S
authors.lastname: Waldegger
authors.forename: B
authors.initials: B
authors.lastname: Tümmler
authors.forename: M E
authors.initials: ME
authors.lastname: Egan
authors.forename: J P
authors.initials: JP
authors.lastname: Geibel
authors.forename: R
authors.initials: R
authors.lastname: Kandolf
authors.forename: F
authors.initials: F
authors.lastname: Lang
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D053503:Epithelial Sodium Channels; D006801:Humans; D017403:In Situ Hybridization; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D018075:RNA, Complementary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C505032:CFTR protein, human; D053503:Epithelial Sodium Channels; D018075:RNA, Complementary; D012333:RNA, Messenger; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D015056:1-Methyl-3-isobutylxanthine