Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney
Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney
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DOI：
10.1042/bsr20171243
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发表时间：
2018-02-28
影响因子：
4
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
--
作者：
Nomura, Naohiro;Shoda, Wakana;Uchida, Shinichi
氯化钠共转运体(NCC)被认为是调节钾平衡的关键分子。体外研究了NCC在低细胞外钾浓度下的调控机制。这些研究表明，超极化导致氯离子外流增加，导致氯离子敏感的非赖氨酸激酶(WNK)及其下游分子激活，包括STE20/SPS1相关的脯氨酸/丙氨酸丰富的激酶(SPAK)和NCC。然而，这一机制还没有在体内进行研究。在此之前，我们开发了Barttin亚型小鼠(BSND(neo/neo)小鼠)，表达非常低水平的barttin和ClC-K通道，因为barttin是ClC-K的一个必不可少的ss亚基。与BSND(-/-)小鼠相比，Bsndneo/neo小鼠存活到成年。在BSND(neo/neo)小鼠中，与野生型(WT)小鼠相比，低钾饮食后SPAK和NCC的激活明显受损。在体外肾切片实验中，BSND(neo/neo)小鼠在低钾介质中pNCC和Spak的增加也受到抑制。此外，在喂食高盐低钾饮食的WT小鼠中观察到血压升高，这在Bsndneo/neo小鼠中并不明显。因此，我们的研究提供了体内证据，表明在低钾饮食下，ClC-K和Barttin在WNK4-Spak-NCC级联激活和血压调节中发挥重要作用。
The sodium chloride cotransporter (NCC) has been identified as a key molecule regulating potassium balance. The mechanisms of NCC regulation during low extracellular potassium concentrations have been studied in vitro. These studies have shown that hyperpolarization increased chloride efflux, leading to the activation of chloride-sensitive with-no-lysine kinase (WNK) kinases and their downstream molecules, including STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NCC. However, this mechanism was not studied in vivo. Previously, we developed the barttin hypomorphic mouse (Bsnd(neo/neo) mice), expressing very low levels of barttin and ClC-K channels, because barttin is an essential ss-subunit of ClC-K. In contrast with Bsnd(-/-) mice, Bsndneo/neo mice survived to adulthood. In Bsnd(neo/neo) mice, SPAK and NCC activation after consuming a low-potassium diet was clearly impaired compared with that in wild-type (WT) mice. In ex vivo kidney slice experiment, the increase in pNCC and SPAK in low-potassium medium was also impaired in Bsnd(neo/neo) mice. Furthermore, increased blood pressure was observed in WT mice fed a high-salt and low-potassium diet, which was not evident in Bsndneo/neo mice. Thus, our study provides in vivo evidence that, in response to a low-potassium diet, ClC-K and barttin play important roles in the activation of the WNK4-SPAK-NCC cascade and blood pressure regulation.