Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule
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DOI：
10.1038/ng1877
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发表时间：
2006-10-01
期刊：
影响因子：
30.8
通讯作者：
Lifton, Richard P.
中科院分区：
文献类型：
--
作者：
Lalioti, Maria D.;Zhang, Junhui;Lifton, Richard P.
控制复杂系统动态平衡的机制一直难以捉摸，但可以通过扰乱系统行为的突变来阐明。编码激酶WNK4的基因突变会导致假性醛固酮缺乏症II型(PHAII)，这是一种以高血压和高钾为特征的综合征。我们发现，在转基因野生型(TgWnk4(WT))或PHAII突变体(TgWnk4(PHAII))Wnk4的小鼠中，生理学发生了相反方向的变化：TgWnk4(PHAII)小鼠有更高的血压、高钾血症、高钙尿和明显的远端曲管(DCT)增生，而TgWnk4(WT)小鼠的情况正好相反。DCT(NCC)钠氯共转运体(NCC)的遗传缺陷逆转了TgWnk4PHAII小鼠的表型，表明PHAII突变的影响是由于NCC活性改变所致。这些发现表明，Wnk4是一个分子开关，通过影响NCC来改变DCT的质量和功能，从而调节盐重吸收和K+分泌之间的平衡。
The mechanisms that govern homeostasis of complex systems have been elusive but can be illuminated by mutations that disrupt system behavior. Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. We show that physiology in mice transgenic for genomic segments harboring wild-type (TgWnk4(WT)) or PHAII mutant (TgWnk4(PHAII)) Wnk4 is changed in opposite directions: TgWnk4(PHAII) mice have higher blood pressure, hyperkalemia, hypercalciuria and marked hyperplasia of the distal convoluted tubule (DCT), whereas the opposite is true in TgWnk4(WT) mice. Genetic deficiency for the Na-Cl cotransporter of the DCT (NCC) reverses phenotypes seen in TgWnk4PHAII mice, demonstrating that the effects of the PHAII mutation are due to altered NCC activity. These findings establish that Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K+ secretion by altering the mass and function of the DCT through its effect on NCC.