Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 28, Issue 1, Pages 209-217Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2016010085
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Funding
- l'Agence Nationale de la Recherche (ANR) [ANR BLANC 14-CE12-0013-01/HYPERSCREEN]
- grant ECOS/CONYCIT France-Chile
- grant CHLORBLOCK from the Initiative d'excellence Sorbonne Paris Cite
- Fondation du Rein
- Interdisziplinares Zentrum fur klinische Forschung Jena
- Else-Kroner-Fresenius foundation [2014_A126]
- Deutsche Forschungsgemeinschaft [HU 800/7-1]
- French Nephrology Society sous egide de la Fondation pour la Recherche Medicale
- ANR [ANR 15-CE14-0024-02/ConTarKiD]
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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 CIC-Kb/K2, two chloride channels from the CIC family, or by KCI cotransporters from the SLC1 2 gene family. Nevertheless, the localization and role of CIC-K channels is not fully resolved. Because inactivating mutations in CIC-Kb/K2 cause Bartter syndrome, a disease that mimics the effects of the loop diuretic furosemide, CIC-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 CIC-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 CIC-K2 is the main basolateral chloride channel in the thick ascending limb and in the aldosterone-sensitive distal nephron. Accordingly, CIC-K2 KO mice did not exhibit the natriuretic response to furosemide and exhibited a severely blunted response to thiazide. We conclude that CIC-Kb/K2 is critical for salt absorption not only by the thick ascending limb, but also by the distal convoluted tubule.
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