Department of Nephrology, Tokyo Medical and Dental University, Japan.
Hum Mol Genet. 2009 Oct 15;18(20):3978-86. doi: 10.1093/hmg/ddp344. Epub 2009 Jul 24.
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.
我们最近生成了 Wnk4(D561A/+) 敲入小鼠，并发现假性醛固酮减少症 II 型的一个主要发病机制是突变 WNK4 激活 OSR1/SPAK 激酶-钠氯共转运蛋白 (NCC) 磷酸化级联。然而，野生型 WNK4 对钠排泄和血压调节的生理作用，以及在该级联中野生型 WNK4 是正向还是负向作用，仍有待确定。在本研究中，我们通过删除 Wnk4 基因的外显子 7 生成了 WNK4 低功能小鼠。这些小鼠没有出现低钾血症和代谢性碱中毒，但在低盐饮食下确实表现出低血压和增加的钠和钾排泄。与野生型同窝仔相比，突变小鼠中 OSR1/SPAK 和 NCC 的磷酸化明显减少。ROMK 和 Maxi K 的蛋白水平没有改变，但上皮钠通道似乎被激活，作为 NCC 功能降低的补偿机制。因此，野生型 WNK4 是 WNK-OSR1/SPAK-NCC 级联的正向调节剂，WNK4 是抗高血压药物的潜在靶点。
