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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >WNK1 kinase isoform switch regulates renal potassium excretion
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WNK1 kinase isoform switch regulates renal potassium excretion

机译：WNK1激酶同工型开关调节肾钾排泄

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摘要

Members of the WNK family of serine/threonine kinases have been implicated as important modulators of salt homeostasis, regulating the balance between renal sodium reabsorption and potassium excretion. Gain-of-expression mutations in the WNK1 gene uncouple Na~+ and K~+ balance and cause a familial disorder of diminished renal potassium excretion, excessive sodium retention, and hypertension (pseudohypoaldosteronism type Ⅱ or Gordon's syndrome). Alternative splicing of the WNK1 gene produces a kidney-specific short form of WNK1 (KS-WNK1) and a more ubiquitous long form (L-WNK1), but it is not clear how either of these isoforms influence renal potassium excretion. Here we demonstrate that KS-WNK1 and L-WNK1 converge in a pathway to regulate the renal outer-medullary K~+ channel, Kir1.1. Reconstitution studies in Xenopus oocytes reveal that L-WNK1 significantly inhibits Kir1.1 by reducing cell surface localization of the channel. A catalytically inactive L-WNK1 mutant has no inhibitory effect on Kir1.1, indicating that channel inhibition depends on kinase activity. KS-WNK1, lacking an intact kinase domain, does not directly alter Kir1.1. Instead, KS-WNK1 negatively regulates L-WNK1 to release Kir1.1 from inhibition. Acute dietary potassium loading increases the relative abundance of KS-WNK1 to L-WNK1 transcript and protein in the kidney, indicating that physiologic up-regulation of Kir1.1 activity involves a WNK1 isoform switch and KS-WNK1 -mediated release from L-WNK1 inhibition. Thus, these observations provide evidence for the physiological regulation of Na~+ and K~+ balance by a kinase isoform switch mechanism.
机译：WNK丝氨酸/苏氨酸激酶家族成员被认为是盐稳态的重要调节剂，调节肾脏钠吸收和钾排泄之间的平衡。 WNK1基因的表达增益突变使Na〜+和K〜+平衡解耦，并导致家族性疾病，即肾脏钾排泄减少，钠过多滞留和高血压（PseudohypoaldosteronismⅡ型或Gordon综合征）。 WNK1基因的可变剪接产生了肾脏特异性的WNK1短形式（KS-WNK1）和更普遍的长形式（L-WNK1），但尚不清楚这两种同工型如何影响肾脏的钾排泄。在这里，我们证明了KS-WNK1和L-WNK1会以一条途径调节肾脏的肾外K +通道Kir1.1。在非洲爪蟾卵母细胞中的重建研究表明L-WNK1通过减少通道的细胞表面定位来显着抑制Kir1.1。催化失活的L-WNK1突变体对Kir1.1没有抑制作用，表明通道抑制取决于激酶活性。缺少完整的激酶结构域的KS-WNK1不会直接改变Kir1.1。而是，KS-WNK1负调控L-WNK1从抑制释放Kir1.1。急性饮食钾负荷增加肾脏中KS-WNK1与L-WNK1转录本和蛋白质的相对丰度，表明Kir1.1活性的生理上调涉及WNK1同工型转换和KS-WNK1介导的从L-WNK1释放抑制。因此，这些观察为通过激酶同工型转换机制对Na +和K +平衡的生理调节提供了证据。

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