title: In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron.
abstract: The epithelial sodium channel (ENaC) is rate limiting for Na(+) absorption in the aldosterone-sensitive distal nephron comprising the late distal convoluted tubule (DCT2), the connecting tubule (CNT), and the entire collecting duct. Liddle syndrome (pseudohyperaldosteronism), a severe form of salt-sensitive hypertension, is caused by gain-of-function mutations of ENaC, but the precise tubular site of increased ENaC function is unknown. In the cortical collecting duct (CCD), ENaC is known to be regulated by aldosterone. In contrast, we recently reported aldosterone-independent ENaC regulation in the early part of the aldosterone-sensitive distal nephron. Here, we investigated ENaC function in the transition zone of DCT2/CNT or CNT/CCD microdissected from mice homozygous for Liddle syndrome mutation or from wild-type control mice. Whole-cell patch-clamp recordings were used to measure amiloride-sensitive ENaC currents in nephron fragments from mice maintained on different sodium diets to vary plasma aldosterone levels. Our data indicate that in mice with Liddle syndrome, the primary site of increased Na(+) reabsorption is the DCT2/CNT. In addition, increased aldosterone responsiveness of ENaC in CNT/CCD may contribute to salt-sensitive hypertension in Liddle syndrome. Single channel properties of ENaC were similar in Liddle syndrome mutation and wild-type mice, but ENaC expression at the apical membrane was increased in Liddle syndrome mutation when compared with wild-type mice, in particular, in animals maintained on a high salt diet. Our findings highlight the importance of ENaC function and regulation in the early part of the aldosterone-sensitive distal nephron for the maintenance of sodium balance and blood pressure control.
authors.affiliation: From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Viatcheslav
authors.initials: V
authors.lastname: Nesterov
authors.affiliation: From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Krueger
authors.affiliation: From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Bertog
authors.affiliation: From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Dahlmann
authors.affiliation: From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Palmisano
authors.affiliation: From the Institut für Zelluläre und Molekulare Physiologie (V.N., B.K., M.B., C.K.), Universitätsklinikum Erlangen, Medizinische Klinik 4-Nephrologie und Hypertensiologie (A.D.), and Optical Imaging Center Erlangen (OICE) (R.P.), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. christoph.korbmacher@fau.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Korbmacher
mesh_terms: D000450:Aldosterone / Q000097:blood*; D000818:Animals; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D056929:Liddle Syndrome / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009399:Nephrons / Q000378:metabolism; D012680:Sensitivity and Specificity; D012982:Sodium, Dietary / Q000494:pharmacology*
chemical_list: D053503:Epithelial Sodium Channels; C507049:Scnn1b protein, mouse; D012982:Sodium, Dietary; D000450:Aldosterone
keywords: ENaC; Liddle syndrome; aldosterone; microdissected renal tubules; patch-clamp technique; pseudohyperaldosteronism; salt-sensitive hypertension