Clinical importance of potassium intake and molecular mechanism of potassium regulation

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 β-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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10157-019-01766-x) contains supplementary material, which is available to authorized users.