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]) 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) 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.

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.