The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway
The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway
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DOI：
10.1242/jcs.029223
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发表时间：
2008-10-15
影响因子：
4
通讯作者：
Alessi, Dario R.
中科院分区：
文献类型：
--
作者：
Richardson, Ciaran;Alessi, Dario R.
最近研究表明，WNK [with-no-K（Lys）]激酶（WNK 1、WNK 2、WNK 3和WNK 4）在盐稳态和血压控制中具有重要作用。这篇评论集中于最近的发现，这些发现揭示了一种由WNK激酶控制的新型信号转导网络的骨架。在高渗或低渗低Cl（-）条件下，WNK亚型被激活，随后磷酸化并激活相关蛋白激酶SPAK和OSR 1。SPAK和OSR 1磷酸化并激活离子共转运蛋白，包括NCC、NKCC 1和NKCC 2，它们是常用的降压噻嗪类利尿剂和环利尿剂药物的靶点。WNK 1、WNK 4、NCC和NKCC 2突变导致人类遗传性血压综合征的发现突出了这些酶的重要性。我们认为，这些新发现表明SPAK和OSR 1是治疗高血压的有希望的药物靶点，因为抑制这些酶将降低NCC和NKCC 2活性，从而抑制肾盐重吸收。我们还讨论了这一研究领域中尚未解决的和有争议的问题。
It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel signal-transduction network that is controlled by WNK kinases. Under hyperosmotic or hypotonic low-Cl(-) conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK and OSR1. SPAK and OSR1 phosphorylate and activate ion co-transporters that include NCC, NKCC1 and NKCC2, which are targets for the commonly used blood-pressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.