title: A SPAK isoform switch modulates renal salt transport and blood pressure.
abstract: The renal thick ascending limb (TAL) and distal convoluted tubule (DCT) play central roles in salt homeostasis and blood pressure regulation. An emerging model suggests that bumetanide- and thiazide-sensitive NaCl transporters (NKCC2 and NCC) along these segments are phosphorylated and activated by WNK kinases, via SPAK and OSR1. Here, we show that a kidney-specific SPAK isoform, which lacks the kinase domain, inhibits phosphorylation of NCC and NKCC2 by full-length SPAK in vitro. Kidney-specific SPAK is highly expressed along the TAL, whereas full-length SPAK is more highly expressed along the DCT. As predicted from the differential expression, SPAK knockout in animals has divergent effects along TAL and DCT, with increased phosphorylated NKCC2 along TAL and decreased phosphorylated NCC along DCT. In mice, extracellular fluid volume depletion shifts SPAK isoform abundance to favor NaCl retention along both segments, indicating that a SPAK isoform switch modulates sodium avidity along the distal nephron.
authors: Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239-3098, USA. mccormij@ohsu.edu
authors: James A
authors: JA
authors: McCormick
authors: Kerim
authors: K
authors: Mutig
authors: Joshua H
authors: JH
authors: Nelson
authors: Turgay
authors: T
authors: Saritas
authors: Ewout J
authors: EJ
authors: Hoorn
authors: Chao-Ling
authors: CL
authors: Yang
authors: Shaunessy
authors: S
authors: Rogers
authors: Joshua
authors: J
authors: Curry
authors: Eric
authors: E
authors: Delpire
authors: Sebastian
authors: S
authors: Bachmann
authors: David H
authors: DH
authors: Ellison
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D045604:Extracellular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000378:metabolism*; D008138:Loop of Henle / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012492:Salts / Q000378:metabolism; D015398:Signal Transduction; D012965:Sodium Chloride / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000502:physiology*
chemical_list: D007527:Isoenzymes; D011955:Receptors, Drug; D012492:Salts; C578715:Slc12a1 protein, mouse; C578875:Slc12a3 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D012965:Sodium Chloride; C486407:Stk39 protein, mouse; C534421:OXSR1 protein, mouse; D017346:Protein Serine-Threonine Kinases