Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone
Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone
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DOI：
10.1038/ki.2008.451
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发表时间：
2008-12-01
影响因子：
19.6
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
--
作者：
Chiga, Motoko;Rai, Tatemitsu;Uchida, Shinichi
假性醛固酮缺乏症II型(PHAII)是由WNK1和WNK4基因突变引起的。在这种疾病的小鼠模型中，Wnk4 D561a的突变体被敲入，发现氯化钠共转运体(NCC)的磷酸化增加，转运体集中在远端小管的顶膜上。此外，我们最近还发现，其他一些蛋白，如氧化应激反应蛋白-1/STE20/SPS1相关的富含丙氨酸的丙氨酸激酶(OSR1/SPAK)，在这些小鼠中也表现出明显的磷酸化。在这里，我们确定了这种激酶级联是否受饮食盐摄入量的调节。我们发现，NCC和OSR1/Spak的磷酸化状态在低盐饮食中增加，在高盐饮食中降低；这一调节在敲入小鼠中完全消失。增加的磷酸化可被螺内酯逆转，这种降低的磷酸化可被外源性醛固酮逆转。这些研究表明，WNK-OSR1/SPAK-NCC级联可能是肾脏中一种新的醛固酮效应系统。
Pseudohypoaldosteronism type II (PHAII) is caused by mutations in the WNK1 and WNK4 genes (WNK with-no-lysine kinase). In a mouse model of this disease where a mutant of Wnk4 D561A was knocked in, increased phosphorylation of the sodium chloride cotransporter (NCC) was found and the transporter was concentrated on the apical membrane of the distal tubules. In addition, we recently found that other kinases, such as the oxidative stress response kinase-1/STE20/SPS1-related proline alanine-rich kinase (OSR1/SPAK), also showed increased phosphorylation in these mice. Here we determined whether this kinase cascade is regulated by dietary salt intake. We found that the phosphorylation states of NCC and OSR1/SPAK were increased by low-salt diets and decreased by high-salt diets; a regulation completely lost in the knock-in mice. Increased phosphorylation was reversed by spironolactone and this decreased phosphorylation was reversed by administration of exogenous aldosterone. These studies suggest that that the WNK-OSR1/SPAK-NCC cascade may be a novel effector system of aldosterone action in the kidney.