Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 594, Issue 21, Pages 6319-6331Publisher
WILEY-BLACKWELL
DOI: 10.1113/JP272504
Keywords
potassium; sodium transport; signal transduction
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Funding
- European Union [608847]
- National Institutes of Health [NIH R01DK084059]
- German Research Foundation DFG [SFB699]
- Swiss National Centre for Competence in Research 'Kidney.CH'
- Swiss National Science Foundation [310030_143929/1, 310030_159765/1]
- COST Action ADMIRE [BM1301]
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A high dietary potassium (K+) intake causes a rapid dephosphorylation, and hence inactivation, of the thiazide-sensitive NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Based on experiments in heterologous expression systems, it was proposed that changes in extracellular K+ concentration ([K+](ex)) modulate NCC phosphorylation via a Cl--dependent modulation of the with no lysine (K) kinases (WNK)-STE20/SPS-1-44 related proline-alanine-rich protein kinase (SPAK)/oxidative stress-related kinase (OSR1) kinase pathway. We used the isolated perfused mouse kidney technique and ex vivo preparations of mouse kidney slices to test the physiological relevance of this model on native DCT. We demonstrate that NCC phosphorylation inversely correlates with [K+](ex), with the most prominent effects occurring around physiological plasma [K+]. Cellular Cl- conductances and the kinases SPAK/OSR1 are involved in the phosphorylation of NCC under low [K+](ex). However, NCC dephosphorylation triggered by high [K+](ex) is neither blocked by removing extracellular Cl-, nor by the Cl- channel blocker 4,4-diisothiocyano-2,2-stilbenedisulphonic acid. The response to [K+](ex) on a low extracellular chloride concentration is also independent of significant changes in SPAK/OSR1 phosphorylation. Thus, in the native DCT, [K+](ex) directly and rapidly controls NCC phosphorylation by Cl--dependent and independent pathways that involve the kinases SPAK/OSR1 and a yet unidentified additional signalling mechanism.
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