CLC Chloride channels and diseases

我们已经分离并鉴定了几种CIC氯离子通道。在这项研究中，我们重点研究了两个肾脏特异的CIC氯通道，ClC-K1和ClC-K2。CIC-K1和CLC-K2具有很高的同源性，在多种组织中仅在肾脏中表达。最近，人类与大鼠CIC-K2同源基因CLCNKB被发现在Bartter综合征患者中发生突变，为了探讨CLCNKB基因突变患者Bartter综合征的发病机制，我们试图通过原位杂交来确定CLC-K2在肾脏中的准确定位。ClC-K2表达于远端曲管、连接管、皮质集合管和Henle‘s环髓质粗升支。这一结果表明CLC-K2参与了这些远端肾单位段的跨上皮氯的运输。为了确定CLC-K1在肾脏中的生理作用，我们建立了CLC-K1基因敲除小鼠。他们没有表现出巴特综合征，不像ClC-K2突变，但有肾源性尿崩症。这一结果清楚地证明了。CLC-K1在体内的作用，即尿药浓度。

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.