Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms
Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms
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DOI：
10.1073/pnas.0510609103
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发表时间：
2006-01-31
影响因子：
11.1
通讯作者：
Huang, CL
中科院分区：
文献类型：
--
作者：
Lazrak, A;Liu, Z;Huang, CL
WNK激酶是具有催化赖氨酸的非典型位置的丝氨酸-苏氨酸激酶。内含子缺失和普遍存在的长WNK 1转录物表达增加导致2型假性醛固酮减少症（PHA II），其特征为高血压和高钾血症。在这里，我们报告说，长WNK 1抑制ROMK 1刺激其内吞作用。长WNK 1对ROMK的抑制与WNK 4协同，但不依赖于WNK 4。缺少N-末端1-437个氨基酸的WNK 1的较小转录物在肾脏中高度表达。KS-WNK 1（肾特异性，KS）的表达是否在PHA II中改变尚不清楚。我们发现KS-WNK 1不抑制ROMK 1，但逆转了长WNK 1对ROMK 1的抑制。与KS-WNK 1缺乏抑制一致，我们发现长WNK 1的氨基酸1-491足以抑制ROMK。饮食K+限制通过刺激内吞作用降低肾皮质集合管中的ROMK丰度，内吞作用是K+缺乏期间K+保护的重要适应性反应。我们发现，大鼠K+限制增加了整个肾脏长WNK 1的转录，而KS-WNK 1的转录减少。因此，KS-WNK 1是长WNK 1的生理拮抗剂。具有PHA II突变的PHA II患者的高钾血症可能至少部分地由长WNK 1表达增加引起，伴或不伴KS-WNK 1表达减少。
WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis. Inhibition of ROMK by long WNK1 was synergistic with, but not dependent on, WNK4. A smaller transcript of WNK1 lacking the N-terminal 1-437 amino acids is expressed highly in the kidney. Whether expression of the KS-WNK1 (kidney-specific, KS) is altered in PHA II is not known. We found that KS-WNK1 did not inhibit ROMK1 but reversed the inhibition of ROMK1 caused by long WNK1. Consistent with the lack of inhibition by KS-WNK1, we found that amino acids 1-491 of the long WNK1 were sufficient for inhibiting ROMK. Dietary K+ restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K+ during K+ deficiency. We found that K+ restriction in rats increased whole-kidney transcript of long WNK1 while decreasing that of KS-WNK1. Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1.