Sodium-Calcium Exchanger 1 Is The Key Molecule For Urinary Potassium Excretion Against Acute Hyperkalemia

The sodium (Na+)-chloride cotransporter (NCC) expressed in the distal convoluted tubule (DCT) is a key molecule regulating urinary Na(+)and potassium (K+) excretion. We previously reported that high-K(+)load rapidly dephosphorylated NCC and promoted urinary K(+)excretion in mouse kidneys. This effect was inhibited by calcineurin (CaN) and calmodulin inhibitors. However, the detailed mechanism through which high-K(+)signal results in CaN activation remains unknown. We used Flp-In NCC HEK293 cells and mice to evaluate NCC phosphorylation. We analyzed intracellular Ca(2+)concentration ([Ca2+](in)) using live cell Ca(2+)imaging in HEK293 cells. We confirmed that high-K+-induced NCC dephosphorylation was not observed without CaN using Flp-In NCC HEK29 cells. Extracellular Ca(2+)reduction with a Ca(2+)chelator inhibited high-K+-induced increase in [Ca2+](in)and NCC dephosphorylation. We focused on Na+/Ca(2+)exchanger (NCX) 1, a bidirectional regulator of cytosolic Ca(2+)expressed in DCT. We identified that NCX1 suppression with a specific inhibitor (SEA0400) or siRNA knockdown inhibited K+-induced increase in [Ca2+](in)and NCC dephosphorylation. In a mouse study, SEA0400 treatment inhibited K+-induced NCC dephosphorylation. SEA0400 reduced urinary K(+)excretion and induced hyperkalemia. Here, we identified NCX1 as a key molecule in urinary K(+)excretion promoted by CaN activation and NCC dephosphorylation in response to K(+)load.