title: WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia.
abstract: Mutations in the serine-threonine kinase WNK4 [with no lysine (K) 4] cause pseudohypoaldosteronism type II, a Mendelian disease featuring hypertension with hyperkalemia. In the kidney, WNK4 regulates the balance between NaCl reabsorption and K(+) secretion via variable inhibition of the thiazide-sensistive NaCl cotransporter and the K(+) channel ROMK. We now demonstrate expression of WNK4 mRNA and protein outside the kidney. In extrarenal tissues, WNK4 is found almost exclusively in polarized epithelia, variably associating with tight junctions, lateral membranes, and cytoplasm. Epithelia expressing WNK4 include sweat ducts, colonic crypts, pancreatic ducts, bile ducts, and epididymis. WNK4 is also expressed in the specialized endothelium of the blood-brain barrier. These epithelia and endothelium all play important roles in Cl(-) transport. Because WNK4 is known to regulate renal Cl(-) handling, we tested WNK4's effect on the activity of mediators of epithelial Cl(-) flux whose extrarenal expression overlaps with WNK4. WNK4 proved to be a potent inhibitor of the activity of both the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) and the Cl(-)/base exchanger SLC26A6 (CFEX) (>95% inhibition of NKCC1-mediated (86)Rb influx, P < 0.001; >80% inhibition of CFEX-mediated [(14)C] formate uptake, P < 0.001), mediators of Cl(-) flux across basolateral and apical membranes, respectively. In contrast, WNK4 showed no inhibition of pendrin, a related Cl(-)/base exchanger. These findings indicate a general role for WNK4 in the regulation of electrolyte flux in diverse epithelia. Moreover, they reveal that WNK4 regulates the activities of a diverse group of structurally unrelated ion channels, cotransporters, and exchangers.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gimenez
authors.forename: Hatim
authors.initials: H
authors.lastname: Hassan
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Wilson
authors.forename: Robert D
authors.initials: RD
authors.lastname: Wong
authors.forename: Biff
authors.initials: B
authors.lastname: Forbush
authors.forename: Peter S
authors.initials: PS
authors.lastname: Aronson
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity; D002712:Chlorides / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D000076988:Sulfate Transporters; D014982:Xenopus laevis
chemical_list: D002352:Carrier Proteins; D002712:Chlorides; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C578877:SLC12A2 protein, human; C085609:SLC26A4 protein, human; C439529:SLC26A6 protein, human; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D000076988:Sulfate Transporters; C499024:Prkwnk4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C433806:WNK4 protein, human