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J Am Soc Nephrol. 2017 Jan;28(1):209-217. doi: 10.1681/ASN.2016010085. Epub 2016 Jun 22.

The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron.

Author information

1
Institut für Humangenetik, University Hospital Jena, Friedrich-Schiller-Universität, Jena, Germany.
2
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.
3
Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.
4
Centro de Estudios Científicos, Valdivia, Chile.
5
Service de Néphrologie, Hôpital Felix Guyon, Centre Hospitalier Universitaire de la Réunion, St Denis, Ile de la Réunion, France.
6
Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück Centrum für Molekulare Medizin, Berlin, Germany.
7
Faculté de Médecine, Université Paris-Descartes, Paris, France.
8
Centre National de la Recherche Scientifique, Paris, France; and.
9
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.
10
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.
11
Département de Physiologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.

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.

KEYWORDS:

Bartter-s syndrome; chloride channels; ion transport; transgenic mouse

PMID:
27335120
PMCID:
PMC5198284
DOI:
10.1681/ASN.2016010085
[Indexed for MEDLINE]
Free PMC Article

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