title: Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride.
abstract: Dietary potassium deficiency, common in modern diets, raises blood pressure and enhances salt sensitivity. Potassium homeostasis requires a molecular switch in the distal convoluted tubule (DCT), which fails in familial hyperkalemic hypertension (pseudohypoaldosteronism type 2), activating the thiazide-sensitive NaCl cotransporter, NCC. Here, we show that dietary potassium deficiency activates NCC, even in the setting of high salt intake, thereby causing sodium retention and a rise in blood pressure. The effect is dependent on plasma potassium, which modulates DCT cell membrane voltage and, in turn, intracellular chloride. Low intracellular chloride stimulates WNK kinases to activate NCC, limiting potassium losses, even at the expense of increased blood pressure. These data show that DCT cells, like adrenal cells, sense potassium via membrane voltage. In the DCT, hyperpolarization activates NCC via WNK kinases, whereas in the adrenal gland, it inhibits aldosterone secretion. These effects work in concert to maintain potassium homeostasis.
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA; Department of Nephrology, Xinhua Hostpital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCormick
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Lazelle
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Meermeier
authors.affiliation: Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Dominic A
authors.initials: DA
authors.lastname: Siler
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Hae J
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA; VA Portland Health Care System, Portland, OR 97239, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Cohen
authors.affiliation: Department of Physiology and Biophysics, Weil Medical College, New York, NY 10065, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Weinstein
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA; VA Portland Health Care System, Portland, OR 97239, USA.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA; VA Portland Health Care System, Portland, OR 97239, USA. Electronic address: ellisond@ohsu.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D004573:Electrolytes / Q000652:urine*; D006801:Humans; D007686:Kidney Tubules, Distal / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D011188:Potassium / Q000097:blood / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D017419:Potassium, Dietary / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000378:metabolism / Q000473:pathology; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D064486:Solute Carrier Family 12, Member 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000098854:Kcnj10 Channel
chemical_list: D002712:Chlorides; D004573:Electrolytes; D000098854:Kcnj10 Channel; D015778:Minor Histocompatibility Antigens; D024661:Potassium Channels, Inwardly Rectifying; D017419:Potassium, Dietary; C578875:Slc12a3 protein, mouse; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; C499024:Prkwnk4 protein, mouse; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse; D011188:Potassium