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 (Bsndneo/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.
Keywords: Hypertension; Potassium; Sodium–chloride cotransporter.