CLC Chloride channels and diseases

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We have isoleted and characterized several CIC chloride channels. In this study, we focused on the two kidney-specific CIC chloride channels, ClC-K1 and .ClC-K2. CIC-K1 and ClC-K2 are very homougous each other, and exclusively expressed in the kidney among varius tissues. Recently, the CLCNKB gene, a human homologue of rat CIC-K2, was found to be mutated in the patients with Bartter's syndrome.To explore the pathogenesis of Bartter's syndrome in patients having mutations in the CLCNKB gene, we tried to determine the exact localization of ClC-K2 in the kidney by in situ hybridization. ClC-K2 are expressed in the distal convoluted tubules, connecting ducts, cortical collecting ducts, and medullary thick ascending limb of Henle's loop. This result suggests that ClC-K2 is involved in the transepithelial chloride transport in these distal nephron segments.To determine the physiological role of ClC-K1 in the kidney, we generated ClC-K1 knock out mice. They did not show Bartter's syndrome unlike the mutation of ClC-K2 but had nephrogenic diabetes insipidus. This result clearly established the. role of ClC-K1 in vivo, i.e. urinary concentration.