Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure
Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure
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DOI：
10.1093/hmg/ddp344
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发表时间：
2009-10-15
影响因子：
3.5
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
--
作者：
Ohta, Akihito;Rai, Tatemitsu;Uchida, Shinichi
我们最近产生的Wnk 4（D561 A/+）敲入小鼠，发现假性醛固酮减少症II型的主要发病机制是激活的OSR 1/SPAK激酶-NaCl协同转运（NCC）磷酸化级联突变WNK 4。然而，野生型WNK 4在Na排泄和血压调节中的生理作用，以及野生型WNK 4在该级联反应中的作用是积极的还是消极的，仍有待确定。在本研究中，我们通过删除Wnk 4基因的外显子7来产生WNK 4亚型小鼠。这些小鼠没有表现出低钾血症和代谢紊乱，但它们确实表现出低血压和低盐饮食下Na和K排泄增加。与野生型同窝小鼠相比，突变小鼠OSR 1/SPAK和NCC的磷酸化显著降低。ROMK和Maxi K的蛋白水平没有改变，但上皮Na通道似乎被激活作为NCC功能降低的补偿机制。因此，野生型WNK 4是WNK-OSR 1/SPAK-NCC级联反应的正调节因子，并且WNK 4是抗高血压药物的潜在靶点。
We recently generated Wnk4(D561A/+) knockin mice and found that a major pathogenesis of pseudohypoaldosteronism type II was the activation of the OSR1/SPAK kinase-NaCl cotransporter (NCC) phosphorylation cascade by the mutant WNK4. However, the physiological roles of wild-type WNK4 on the regulation of Na excretion and blood pressure, and whether wild-type WNK4 functions positively or negatively in this cascade, remained to be determined. In the present study, we generated WNK4 hypomorphic mice by deleting exon 7 of the Wnk4 gene. These mice did not show hypokalemia and metabolic alkalosis, but they did exhibit low blood pressure and increased Na and K excretion under low-salt diet. Phosphorylation of OSR1/SPAK and NCC was significantly reduced in the mutant mice as compared with their wild-type littermates. Protein levels of ROMK and Maxi K were not changed, but epithelial Na channel appeared to be activated as a compensatory mechanism for the reduced NCC function. Thus, wild-type WNK4 is a positive regulator for the WNK-OSR1/SPAK-NCC cascade, and WNK4 is a potential target of anti-hypertensive drugs.