Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel
Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel
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DOI：
10.1038/5036
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发表时间：
1999-01-01
期刊：
影响因子：
30.8
通讯作者：
Marumo, F
中科院分区：
文献类型：
--
作者：
Matsumura, Y;Uchida, S;Marumo, F
CLC-K1是一种肾脏特异性氯离子通道，可介导内髓中亨利氏袢（tAL）细升支中的跨上皮氯离子转运（1，2）。在逆流增殖系统的被动模型中，tAL中NaCl的转运被认为是尿浓度的一个组成部分（3-5），但没有直接证据表明CLC-K1参与尿浓度。为了分析CLC-K1在体内的生理功能，我们通过靶向基因破坏产生了缺乏CLC-K1的小鼠。Clcnk 1（-/-）小鼠的身体外观正常，但产生的尿液比Clcnk 1（-/-）和Clcnk（+/+）小鼠多约5倍。缺水24小时后，Clcnk 1（-/-）小鼠严重脱水和嗜睡，体重下降约27%。腹膜内注射V2激动剂1-脱氨基-8-D-精氨酸加压素（dDAVP）在Clcnk 1（+/-）和Clcnk 1（+/+）小鼠中诱导尿渗透压增加三倍，而在Clcnk 1（-/-）小鼠中仅观察到最小增加，表明肾源性尿崩症。与Clcnk 1（+/+）和Clcnk 1（+/-）小鼠相反，Clcnk 1（-/-）小鼠中的腔-浴氯化物梯度不产生扩散电势。这些结果表明，CLC-K1在尿浓度中起作用，并且内髓中的逆流系统参与高渗性髓内压的产生和维持。
CLC-K1 is a kidney-specific chloride channel that mediates transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) in the inner medulla(1,2). Transport of NaCl in the tAL is thought to be a component of urinary concentration in a passive model of the countercurrent multiplication system(3-5), but there has been no direct evidence that CLC-K1 is involved in urine concentration. To analyse the physiological function of CLC-K1 in vivo, we generated mice lacking CLC-K1 by targeted gene disruption. Clcnk1(-/-) mice were physically normal appearance, but produced approximately five times more urine than Clcnk1(-/-) and Clcnk(+/+) mice. After 24 hours of water deprivation, Clcnk1(-/-) mice were severely dehydrated and lethargic, with a decrease of approximately 27% in body weight. Intraperitoneal injection of the V2 agonist 1-deamino-8-D-arginine vasopressin (dDAVP) induced a threefold increase in urine osmolarity in Clcnk1(+/-) and Clcnk1(+/+) mice, whereas only a minimal increase was seen in Clcnk1(-/-) mice, indicating nephrogenic diabetes insipidus, After in vitro perfusion of the tAL, the lumen-to-bath chloride gradient did not produce a diffusion potential in Clcnk1(-/-) mice in contrast to Clcnk1(+/+) and Clcnk1(+/-) mice. These results establish that CLC-K1 has a role in urine concentration, and that the countercurrent system in the inner medulla is involved in the generation and maintenance of hypertonic medullary interstitium.