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.