Molecular pathogenesis of pseudohypoaldosteronism type II:: Generation and analysis of a Wnk4D561A/+ knockin mouse model
Molecular pathogenesis of pseudohypoaldosteronism type II:: Generation and analysis of a Wnk4D561A/+ knockin mouse model
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DOI：
10.1016/j.cmet.2007.03.009
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发表时间：
2007-05-01
期刊：
影响因子：
29
通讯作者：
Uchida, Shinichi
中科院分区：
文献类型：
--
作者：
Yang, Sung-Sen;Morimoto, Tetsuji;Uchida, Shinichi
据报道，WNK 1和WNK 4突变可引起II型假性醛固酮减少症（PHAII），这是一种常染色体显性遗传疾病，其特征为高钾血症和高血压。为了阐明PHAII的分子病理生理学，我们产生了呈现PHAII表型的Wnk（4D 561 A/+）敲入小鼠。敲入小鼠显示远端曲小管中磷酸化钠-氯协同转运蛋白（NCC）的顶端表达增加。在敲入小鼠中也观察到激酶OSR 1和SPAK的磷酸化增加。ROMK钾通道的顶端定位和皮质集合管中的跨上皮Cl-渗透性在敲入小鼠中不受影响，而上皮Na+通道（ENaC）的活性增加。然而，这种增加在氢氯噻嗪治疗后并不明显，表明ENaC的调节不是遗传的，而是继发性效应。因此，由WNK 4的错义突变引起的PHAII的发病机制被鉴定为通过激活OSR 1/SPAK-NCC磷酸化级联增加NCC的功能。
WNK1 and WNK4 mutations have been reported to cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder characterized by hyperkalemia and hypertension. To elucidate the molecular pathophysiology of PHAII, we generated Wnk(4D561A/+) knockin mice presenting the phenotypes of PHAII. The knockin mice showed increased apical expression of phosphorylated Na-Cl cotransporter (NCC) in the distal convoluted tubules. Increased phosphorylation of the kinases OSR1 and SPAK was also observed in the knockin mice. Apical localization of the ROMK potassium channel and transepithelial Cl- permeability in the cortical collecting ducts were not affected in the knockin mice, whereas activity of epithelial Na+ channels (ENaC) was increased. This increase, however, was not evident after hydrochlorothiazide treatment, suggesting that the regulation of ENaC was not a genetic but a secondary effect. Thus, the pathogenesis of PHAII caused by a missense mutation of WNK4 was identified to be increased function of NCC through activation of the OSR1/SPAK-NCC phosphorylation cascade.