PLoS ONE (Jan 2020)

Sodium-calcium exchanger 1 is the key molecule for urinary potassium excretion against acute hyperkalemia.

  • Wakana Shoda,
  • Naohiro Nomura,
  • Fumiaki Ando,
  • Hideaki Tagashira,
  • Takahiro Iwamoto,
  • Akihito Ohta,
  • Kiyoshi Isobe,
  • Takayasu Mori,
  • Koichiro Susa,
  • Eisei Sohara,
  • Tatemitsu Rai,
  • Shinichi Uchida

DOI
https://doi.org/10.1371/journal.pone.0235360
Journal volume & issue
Vol. 15, no. 6
p. e0235360

Abstract

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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 Ca2+ concentration ([Ca2+]in) using live cell Ca2+ imaging in HEK293 cells. We confirmed that high-K+-induced NCC dephosphorylation was not observed without CaN using Flp-In NCC HEK29 cells. Extracellular Ca2+ reduction with a Ca2+ chelator inhibited high-K+-induced increase in [Ca2+]in and NCC dephosphorylation. We focused on Na+/Ca2+ exchanger (NCX) 1, a bidirectional regulator of cytosolic Ca2+ 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.