CLC Chloride channels and diseases

我们分离并表征了几个CIC氯离子通道。在本研究中，我们重点研究了两个肾特异性CIC氯离子通道，ClC-K1和。clc - k2。CIC-K1和ClC-K2是同源的，在肾脏的各种组织中均有表达。最近，CLCNKB基因（大鼠CIC-K2的人类同源基因）被发现在Bartter综合征患者中发生突变。为了探讨CLCNKB基因突变患者巴特氏综合征的发病机制，我们试图通过原位杂交确定ClC-K2在肾脏中的确切定位。ClC-K2表达于远曲小管、连接管、皮质集管和Henle’s袢髓质厚升肢。这一结果表明，ClC-K2参与了这些远端肾元段的上皮氯离子转运。为了确定ClC-K1在肾脏中的生理作用，我们制造了ClC-K1敲除小鼠。他们没有表现出与ClC-K2突变不同的巴特氏综合征，但有肾源性尿崩症。这一结果清楚地确立了。ClC-K1在体内的作用，即尿浓度。

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.