Department of Internal Medicine, Division of Nephrology and Hypertension and Molecular Medicine Program, University of Utah and Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA.
Curr Opin Nephrol Hypertens. 2019 Jul;28(4):360-367. doi: 10.1097/MNH.0000000000000502.
This review focuses on the role of intracellular chloride in regulating transepithelial ion transport in the distal convoluted tubule (DCT) in response to perturbations in plasma potassium homeostasis.
Low dietary potassium increases the phosphorylation and activity of the sodium chloride cotransporter (NCC) in the DCT, and vice versa, affecting sodium-dependent potassium secretion in the downstream aldosterone-sensitive distal nephron. In cells, NCC phosphorylation is increased by lowering of intracellular chloride, via activation of the chloride-sensitive with no lysine (WNK)-SPAK/OSR1 (Ste20-related proline/alanine-rich kinase/oxidative stress response) kinase cascade. In-vivo studies have demonstrated pathway activation in the kidney in response to low dietary potassium. A possible mechanism is lowering of DCT intracellular chloride in response to low potassium because of parallel basolateral potassium and chloride channels. Recent studies support a role for these channels in the response of NCC to varying potassium. Studies examining chloride-insensitive WNK mutants, in the Drosophila renal tubule and in the mouse, lend further support to a role for chloride in regulating WNK activity and transepithelial ion transport. Caveats, alternatives, and future directions are also discussed.
Chloride sensing by WNK kinase provides a mechanism to allow coupling of extracellular potassium with NCC phosphorylation and activity to maintain potassium homeostasis.
本篇综述聚焦于细胞内氯离子在调节远曲小管（DCT）跨上皮离子转运中所扮演的角色，该调节作用是对血浆钾离子稳态失调的响应。
低钾饮食增加了 DCT 中的钠离子-氯离子共转运蛋白（NCC）的磷酸化和活性，反之亦然，这影响了下游醛固酮敏感的远端肾单位中钠依赖性钾分泌。在细胞中，NCC 的磷酸化可通过降低细胞内氯离子来增加，其机制为激活氯离子敏感的无赖氨酸（WNK）-丝裂原活化蛋白激酶/氧化应激反应激酶（SPAK/OSR1）激酶级联。在体内研究中，已经证明了低钾饮食会激活肾脏中的这条通路。一种可能的机制是低钾引起 DCT 细胞内氯离子降低，这是由于基底外侧钾和氯离子通道的平行作用。最近的研究支持这些通道在 NCC 对不同钾离子的反应中的作用。在果蝇肾小管和小鼠中研究氯离子不敏感的 WNK 突变体进一步支持氯离子在调节 WNK 活性和跨上皮离子转运中的作用。本文还讨论了注意事项、替代方案和未来方向。
WNK 激酶的氯离子感应提供了一种机制，可将细胞外钾离子与 NCC 磷酸化和活性偶联起来，以维持钾离子稳态。
