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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.
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https://www.hal.inserm.fr/inserm-02448119
Contributor : Marc Paulais <>
Submitted on : Wednesday, January 22, 2020 - 9:39:57 AM
Last modification on : Wednesday, October 14, 2020 - 4:13:17 AM

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J. Christopher Hennings, Olga Andrini, Nicolas Picard, Marc Paulais, Antje Huebner, et al.. The ClC-K2 Chloride Channel Is Critical for Salt Handling in the Distal Nephron. Journal of the American Society of Nephrology, American Society of Nephrology, 2017, 28 (1), pp.209-217. ⟨10.1681/ASN.2016010085⟩. ⟨inserm-02448119⟩

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