title: Extracellular K+rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl--dependent and independent mechanisms.
abstract: High dietary potassium (K+) intake dephosphorylates and inactivates the NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Using several ex vivo models, we show that physiological changes in extracellular K+, similar to those occurring after a K+rich diet, are sufficient to promote a very rapid dephosphorylation of NCC in native DCT cells. Although the increase of NCC phosphorylation upon decreased extracellular K+appears to depend on cellular Cl-fluxes, the rapid NCC dephosphorylation in response to increased extracellular K+is not Cl--dependent. The Cl--dependent pathway involves the SPAK/OSR1 kinases, whereas the Cl-independent pathway may include additional signalling cascades.
  
  
  
  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+]exis neither blocked by removing extracellular Cl-, nor by the Cl-channel blocker 4,4'-diisothiocyano-2,2'-stilbenedisulphonic acid. The response to [K+]exon a low extracellular chloride concentration is also independent of significant changes in SPAK/OSR1 phosphorylation. Thus, in the native DCT, [K+]exdirectly and rapidly controls NCC phosphorylation by Cl--dependent and independent pathways that involve the kinases SPAK/OSR1 and a yet unidentified additional signalling mechanism.
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.|Swiss National Centre of Competence in Research 'Kidney Control of Homeostasis', University of Zurich, Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Penton
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.|Swiss National Centre of Competence in Research 'Kidney Control of Homeostasis', University of Zurich, Zurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Czogalla
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wengi
authors.affiliation: Institute of Physiology, Christian-Albrecht University, Kiel, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Himmerkus
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Loffing-Cueni
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Monique
authors.initials: M
authors.lastname: Carrel
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|Swiss National Centre of Competence in Research 'Kidney Control of Homeostasis', University of Zurich, Zurich, Switzerland.
authors.forename: Renuga Devi
authors.initials: RD
authors.lastname: Rajaram
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.|Swiss National Centre of Competence in Research 'Kidney Control of Homeostasis', University of Zurich, Zurich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Staub
authors.affiliation: Institute of Physiology, Christian-Albrecht University, Kiel, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bleich
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweda
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland. johannes.loffing@anatom.uzh.ch.|Swiss National Centre of Competence in Research 'Kidney Control of Homeostasis', University of Zurich, Zurich, Switzerland. johannes.loffing@anatom.uzh.ch.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D002712:Chlorides; C578875:Slc12a3 protein, mouse; D064486:Solute Carrier Family 12, Member 3; D014157:Transcription Factors; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D011188:Potassium
keywords: potassium; signal transduction; sodium transport