Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo, 113-8519, Japan.
Clin Exp Nephrol. 2019 Oct;23(10):1175-1180. doi: 10.1007/s10157-019-01766-x. Epub 2019 Jul 17.
Potassium (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]) 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.
We investigated the role of the ClC-K2 Cl channel and its β-subunit, barttin, using barttin hypomorphic (Bsnd) 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] activated CaN, which dephosphorylates NCC.
We 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.
钾（K）的摄入与血压密切相关。高钾摄入可降低高血压及其相关死亡率。另一方面，高钾血症会导致致命性心律失常的猝死，也与更高的死亡率有关。在远曲小管表达的肾钠（Na）-氯（Cl）共转运体（NCC）是调节尿钾排泄的关键分子。钾的摄入会影响 NCC 的活性，而 NCC 与盐敏感性高血压有关。低钾饮食会激活 NCC，而高钾负荷会抑制 NCC。细胞外钾浓度（[K]）降低引起的超极化会增加钾和 Cl 的外流，导致 Cl 敏感的无赖氨酸（WNK）激酶及其下游分子，包括 STE20/SPS1 相关脯氨酸/丙氨酸丰富激酶（SPAK）和 NCC 的激活。
我们使用 barttin 低功能（Bsnd）小鼠研究了 ClC-K2 Cl 通道及其β亚基 barttin 的作用，发现这些小鼠在低钾诱导的 NCC 激活和盐敏感性高血压中没有表现出变化。此外，我们发现，高钾负荷抑制 NCC 的机制不同，他克莫司（一种钙调神经磷酸酶[CaN]抑制剂）抑制了高钾诱导的 NCC 去磷酸化和尿钾排泄。高钾负荷和他克莫司处理并未改变 WNK4 和 SPAK 的表达。[K]增加引起的去极化激活了 CaN，使其对 NCC 去磷酸化。
我们得出结论，有两种独立的分子机制控制着 NCC 的激活和 K 的排泄。本综述总结了钾摄入的临床重要性，并解释了 NCC 磷酸化如何在低钾和高钾条件下通过不同的分子机制进行调节。
