title: WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
abstract: Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.forename: Jordan
authors.initials: J
authors.lastname: Angell
authors.forename: Rose
authors.initials: R
authors.lastname: Mitchell
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
mesh_terms: D000818:Animals; D019921:Biotinylation; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D018075:RNA, Complementary / Q000378:metabolism; D011955:Receptors, Drug / Q000235:genetics* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014981:Xenopus
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D018075:RNA, Complementary; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; C578875:Slc12a3 protein, mouse; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor; D004247:DNA; D012964:Sodium; C499024:Prkwnk4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C433806:WNK4 protein, human; C498744:Wnk1 protein, mouse