Clinical importance of potassium intake and molecular mechanism of potassium regulation
Clinical importance of potassium intake and molecular mechanism of potassium regulation
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DOI：
10.1007/s10157-019-01766-x
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发表时间：
2019-07
影响因子：
2.3
通讯作者：
Naohiro Nomura;Wakana Shoda;S. Uchida
中科院分区：
文献类型：
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作者：
Naohiro Nomura;Wakana Shoda;S. Uchida
简介钾 (K+) 摄入量与血压有内在联系。高钾摄入量可降低高血压并降低死亡率。另一方面，高钾血症会导致猝死并伴有致命的心律失常，并且还与较高的死亡率有关。肾钠 (Na+)-氯 (Cl-) 协同转运蛋白 (NCC) 在远曲小管中表达，是调节尿 K+ 排泄的关键分子。 K+摄入量影响NCC的活性，这与盐敏感性高血压有关。限制 K+ 的饮食会激活 NCC，而摄入 K+ 则会抑制 NCC。细胞外 K+ 浓度 ([K+]ex) 降低引起的超极化会增加 K+ 和 Cl− 流出，导致 Cl− 敏感的无赖氨酸 (WNK) 激酶及其下游分子的激活，包括 STE20/SPS1 相关脯氨酸/富含丙氨酸激酶 (SPAK) 和 NCC。结果我们使用 barttin 研究了 ClC-K2 Cl−通道及其 β 亚基 barttin 的作用低形态 (Bsndneo/neo) 小鼠，发现这些小鼠没有表现出低 K+ 诱导的 NCC 激活和盐敏感性高血压。此外，我们发现 K+ 负载对 NCC 的抑制是由另一种机制调节的，即他克莫司（一种钙调神经磷酸酶 [CaN] 抑制剂）抑制高 K+ 诱导的 NCC 去磷酸化和尿 K+ 排泄。 K+负荷和他克莫司处理没有改变WNK4和SPAK的表达。 [K+] 增加诱导去极化，使 CaN 去活化，从而使 NCC 去磷酸化。结论我们得出结论，有两种独立的分子机制控制 NCC 激活和 K+ 排泄。本综述总结了 K+ 摄入的临床重要性，并解释了低 K+ 和高 K+ 条件下 NCC 磷酸化如何通过不同的分子机制进行调节。
IntroductionPotassium (K+) intake is intrinsically linked to blood pressure. High-K+intake decreases hypertension and associated lower mortality. On the other hand, hyperkalemia causes sudden death with fatal cardiac arrhythmia and is also related to higher mortality. Renal sodium (Na+)–chloride (Cl‒) cotransporter (NCC), expressed in the distal convoluted tubule, is a key molecule in regulating urinary K+excretion. K+intake affects the activity of the NCC, which is related to salt-sensitive hypertension. A K+-restrictive diet activates NCC, and K+loading suppresses NCC. Hyperpolarization caused by decreased extracellular K+concentration ([K+]ex) increases K+and Cl‒efflux, leading to the activation of Cl‒-sensitive with-no-lysine (WNK) kinases and their downstream molecules, including STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NCC.ResultsWe investigated the role of the ClC-K2 Cl‒channel and its β-subunit, barttin, using barttin hypomorphic (Bsndneo/neo) mice and found that these mice did not show low-K+-induced NCC activation and salt-sensitive hypertension. Additionally, we discovered that the suppression of NCC by K+loading was regulated by another mechanism, whereby tacrolimus (a calcineurin [CaN] inhibitor) inhibited high-K+-induced NCC dephosphorylation and urinary K+excretion. The K+loading and the tacrolimus treatment did not alter the expression of WNK4 and SPAK. The depolarization induced by increased [K+]exactivated CaN, which dephosphorylates NCC.ConclusionsWe concluded that there were two independent molecular mechanisms controlling NCC activation and K+excretion. This review summarizes the clinical importance of K+intake and explains how NCC phosphorylation is regulated by different molecular mechanisms between the low- and the high-K+condition.