Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.
Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.
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DOI：
10.1038/ki.2015.289
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发表时间：
2016-01
影响因子：
19.6
通讯作者：
Ellison DH
中科院分区：
文献类型：
--
作者：
Terker AS;Zhang C;Erspamer KJ;Gamba G;Yang CL;Ellison DH
膳食缺钾激活噻嗪敏感性氯化钠沿远端肾单位的共转运沿着。这可以部分解释在低钾饮食的个体中观察到的高血压和心血管死亡率。最近的数据表明，血浆钾通过影响细胞内氯直接影响远端肾单位，细胞内氯是无赖氨酸激酶（WNK）-Ste 20 p相关的脯氨酸和丙氨酸丰富激酶（SPAK）途径的抑制剂。由于以前的研究使用极端的饮食操作，我们试图确定钾和NCC之间的关系是否具有生理相关性，并阐明所涉及的机制。我们报告，饮食和血浆钾的适度变化影响噻嗪敏感的钠-氯协同转运蛋白，NCC，在体内。激酶测定研究表明，氯化物抑制WNK 4激酶活性的浓度低于其抑制WNK 1或WNK 3活性的浓度。此外，氯化物抑制WNK 4的范围内的远端细胞氯化物。在哺乳动物细胞中，先前鉴定的WNK氯结合基序的突变将WNK 4对SPAK的作用从抑制性转变为刺激性。WNK 1、3和4中该基序的破坏对NCC具有不同的影响，这与具有不同氯化物敏感性的三种WNK一致。因此，钾对NCC的作用在生理范围内分级，这解释了WNK 4独特的氯离子敏感特性如何使激酶介导钾对NCC的体内作用。
Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low potassium diet. Recent data suggest plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the With no lysine kinase (WNK)-Ste20p-related proline-and alanine-rich kinase (SPAK) pathway. Since previous studies used extreme dietary manipulations, we sought to determine if the relationship between potassium and NCC is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect the thiazide-sensitive sodium-chloride cotransporter, NCC, in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3 and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable kinase mediating effects of potassium on NCC in vivo.