Differential roles of WNK4 in regulation of NCC in vivo.
Differential roles of WNK4 in regulation of NCC in vivo.
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WNK4 在体内 NCC 调节中的不同作用。
DOI：
10.1152/ajprenal.00177.2017
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Huang,Chou-Long
中科院分区：
文献类型：
--
作者：
Yang,Yih-Sheng;Xie,Jian;Yang,Sung-Sen;Lin,Shih-Hua;Huang,Chou-Long
远曲小管中的Na+-Cl盐共转运体在肾−重吸收中起重要作用。目前关于NCC调控机制的假说主要集中在WNK4和细胞内Cl-−浓度([Cl-−]i)。WNKK与Cl-−结合，而与Cl-−结合会降低催化活性。据认为，低K+摄入量下的低钾血症会降低[Cl−]i以激活WNK4，从而通过激活Spak来磷酸化和刺激NCC。然而，NCC活性的增加和顶端氯化钠的进入将减缓[Cl−]i的下降。在低K+饮食下，DCT中的[Cl−]i是否足够低以激活WNK4尚不清楚。此外，增加腔内氯化钠的释放也会刺激NCC并导致转运蛋白的上调。与低K+摄入量不同，腔内氯化钠输出量的增加往往会增加[Cl−]i。因此，我们研究了WNK4和[Cl−]i在调节NCC中的作用。我们产生了Wnk4基因敲除小鼠，并检测了低K+摄入量和增加野生型小鼠的腔内氯化钠输送对NCC的调节。与野生型小鼠相比，Wnk4-KO小鼠NCC的丰度、磷酸化和功能活性显著降低。低K+摄入增加了野生型小鼠的NCC磷酸化和功能活性，但在Wnk4-KO小鼠中没有。与低K+摄入相反，在Wnk4-KO小鼠中，增加腔内氯化钠的供应同样会上调NCC，但不会被取消。结果表明，[Cl−]i对WNK4活性的调节并不是调节NCC的唯一机制。增加的腔内氯化钠释放通过未知的机制(S)上调NCC，这可能超过高[Cl−]i对WNK4的抑制。
The Na+-Cl−cotransporter (NCC) in distal convoluted tubule (DCT) plays important roles in renal NaCl reabsorption. The current hypothesis for the mechanism of regulation of NCC focuses on WNK4 and intracellular Cl−concentration ([Cl−]i). WNK kinases bind Cl−, and Cl−binding decreases the catalytic activity. It is believed that hypokalemia under low K+intake decreases [Cl−]ito activate WNK4, which thereby phosphorylates and stimulates NCC through activation of SPAK. However, increased NCC activity and apical NaCl entry would mitigate the fall in [Cl−]i.Whether [Cl−]iin DCT under low-K+diet is sufficiently low to activate WNK4 is unknown. Furthermore, increased luminal NaCl delivery also stimulates NCC and causes upregulation of the transporter. Unlike low K+intake, increased luminal NaCl delivery would tend to increase [Cl−]i. Thus we investigated the role of WNK4 and [Cl−]iin regulating NCC. We generatedWnk4-knockout mice and examined regulation of NCC by low K+intake and by increased luminal NaCl delivery in knockout (KO) and wild-type mice.Wnk4-KO mice have marked reduction in the abundance, phosphorylation, and functional activity of NCC vs. wild type. Low K+intake increases NCC phosphorylation and functional activity in wild-type mice, but not inWnk4-KO mice. Increased luminal NaCl delivery similarly upregulates NCC, which, contrary to low K+intake, is not abolished inWnk4-KO mice. The results reveal that modulation of WNK4 activity by [Cl−]iis not the sole mechanism for regulating NCC. Increased luminal NaCl delivery upregulates NCC via yet unknown mechanism(s) that may override inhibition of WNK4 by high [Cl−]i.
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影响因子：
13.6
作者：
Luebkemeier, Indra;Machura, Katharina;Kurtz, Armin
通讯作者：
Kurtz, Armin
通过膳食钾摄入量调节肾钾转运。
DOI：
10.1146/annurev.physiol.66.032102.112025
发表时间：
2004
期刊：
Annual review of physiology.
影响因子：
--
作者：
Wang,WenHui
通讯作者：
Wang,WenHui
肾上腺切除兔皮质集合管中活性钾分泌的饮食调节。
DOI：
10.1172/jci110650
发表时间：
1982
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
C. Wingo;D. Seldin;J. Kokko;H. Jacobson
通讯作者：
H. Jacobson
影响因子：
19.6
作者：
Terker AS;Zhang C;Erspamer KJ;Gamba G;Yang CL;Ellison DH
通讯作者：
Ellison DH
DOI：
10.1152/ajprenal.00030.2009
发表时间：
2009-09-01
影响因子：
4.2
作者：
Vallon, Volker;Schroth, Jana;Uchida, Shinichi
通讯作者：
Uchida, Shinichi