期刊
CLINICAL AND EXPERIMENTAL NEPHROLOGY
卷 23, 期 10, 页码 1175-1180出版社
SPRINGER
DOI: 10.1007/s10157-019-01766-x
关键词
Potassium; Hypertension; Sodium-chloride cotransporter
资金
- Japan Society for the Promotion of Science [JP18K15995, JP18058919] Funding Source: Medline
Introduction 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+](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. Results We investigated the role of the ClC-K2 Cl- channel and its beta-subunit, barttin, using barttin hypomorphic (Bsnd(neo/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+](ex) activated CaN, which dephosphorylates NCC. Conclusions 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.
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