title: The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron.
abstract: Chloride transport by the renal tubule is critical for blood pressure (BP), acid-base, and potassium homeostasis. Chloride uptake from the urinary fluid is mediated by various apical transporters, whereas basolateral chloride exit is thought to be mediated by ClC-Ka/K1 and ClC-Kb/K2, two chloride channels from the ClC family, or by KCl cotransporters from the SLC12 gene family. Nevertheless, the localization and role of ClC-K channels is not fully resolved. Because inactivating mutations in ClC-Kb/K2 cause Bartter syndrome, a disease that mimics the effects of the loop diuretic furosemide, ClC-Kb/K2 is assumed to have a critical role in salt handling by the thick ascending limb. To dissect the role of this channel in detail, we generated a mouse model with a targeted disruption of the murine ortholog ClC-K2. Mutant mice developed a Bartter syndrome phenotype, characterized by renal salt loss, marked hypokalemia, and metabolic alkalosis. Patch-clamp analysis of tubules isolated from knockout (KO) mice suggested that ClC-K2 is the main basolateral chloride channel in the thick ascending limb and in the aldosterone-sensitive distal nephron. Accordingly, ClC-K2 KO mice did not exhibit the natriuretic response to furosemide and exhibited a severely blunted response to thiazide. We conclude that ClC-Kb/K2 is critical for salt absorption not only by the thick ascending limb, but also by the distal convoluted tubule.
authors.affiliation: Institut für Humangenetik, University Hospital Jena, Friedrich-Schiller-Universität, Jena, Germany.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Hennings
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 1138, Université Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Andrini
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 1138, Université Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 1138, Université Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Paulais
authors.affiliation: Institut für Humangenetik, University Hospital Jena, Friedrich-Schiller-Universität, Jena, Germany.
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Irma Karen Lopez
authors.initials: IK
authors.lastname: Cayuqueo
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 1138, Université Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bignon
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 1138, Université Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Keck
authors.affiliation: Service de Néphrologie, Hôpital Felix Guyon, Centre Hospitalier Universitaire de la Réunion, St Denis, Ile de la Réunion, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cornière
authors.affiliation: Institut für Humangenetik, University Hospital Jena, Friedrich-Schiller-Universität, Jena, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Böhm
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück Centrum für Molekulare Medizin, Berlin, Germany.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Faculté de Médecine, Université Paris-Descartes, Paris, France.|Centre National de la Recherche Scientifique, Paris, France; and.
authors.forename: Régine
authors.initials: R
authors.lastname: Chambrey
authors.affiliation: Centre National de la Recherche Scientifique Equipe de Recherche Labelisée 8228, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche en Santé 1138, Université Pierre et Marie Curie, Centre de Recherche des Cordeliers, Paris, France; dominique.eladari@inserm.fr Christian.Huebner@med.uni-jena.de.
authors.forename: Jacques
authors.initials: J
authors.lastname: Teulon
authors.affiliation: Institut für Humangenetik, University Hospital Jena, Friedrich-Schiller-Universität, Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France; dominique.eladari@inserm.fr Christian.Huebner@med.uni-jena.de.|Faculté de Médecine, Université Paris-Descartes, Paris, France.|Département de Physiologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000502:physiology*; D018118:Chloride Channels / Q000502:physiology*; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009399:Nephrons / Q000187:drug effects / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism*; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology
chemical_list: D027321:Anion Transport Proteins; D018118:Chloride Channels; C486573:Clcnkb protein, mouse; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D012965:Sodium Chloride; D005665:Furosemide
keywords: Bartter-s syndrome; chloride channels; ion transport; transgenic mouse