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

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.