2007
WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo
Ring AM, Cheng SX, Leng Q, Kahle KT, Rinehart J, Lalioti MD, Volkman HM, Wilson FH, Hebert SC, Lifton RP. WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 4020-4024. PMID: 17360470, PMCID: PMC1805455, DOI: 10.1073/pnas.0611727104.Peer-Reviewed Original ResearchMeSH KeywordsAldosteroneAnimalsColonEpithelial Sodium ChannelsHyperkalemiaHypertensionMiceMice, TransgenicMutationOocytesProtein Serine-Threonine KinasesPseudohypoaldosteronismRatsRenin-Angiotensin SystemXenopus laevisConceptsPseudohypoaldosteronism type IIDistal nephronPHAII-mutant WNK4Wild-type littermatesNa-Cl cotransporterAldosterone systemIntravascular volumeDistal colonSodium balanceElectrolyte homeostasisColonic epitheliumMajor mediatorDiverse mediatorsAltered activityENaC betaWNK4's inhibitionKinase activityIntact C-terminusPHAII-causing mutationsMiceWNK4MediatorsDownstream targetsWNK4 kinase activityENaCAn SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis
Ring AM, Leng Q, Rinehart J, Wilson FH, Kahle KT, Hebert SC, Lifton RP. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 4025-4029. PMID: 17360471, PMCID: PMC1803763, DOI: 10.1073/pnas.0611728104.Peer-Reviewed Original ResearchMeSH KeywordsAldosteroneAmino Acid SequenceAnimalsHumansImmediate-Early ProteinsMiceMolecular Sequence DataOocytesPotassiumPotassium ChannelsProtein Serine-Threonine KinasesSignal TransductionSodium ChannelsXenopus laevisConceptsIntravascular volume depletionNa-Cl cotransporterAldosterone signalingPseudohypoaldosteronism type IIVolume depletionPhysiologic responsesNaCl reabsorptionPHAII-mutant WNK4Steroid hormone aldosteroneRenal outer medullaryRenal NaCl reabsorptionFunctional stateWNK4 mutationsROMK activityHormone aldosteroneOuter medullaryHyperkalemiaSecretionKidneyWild-type WNK4ReabsorptionAldosteroneChannel activityChannel ENaCWNK4
2006
WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1)
Leng Q, Kahle KT, Rinehart J, MacGregor GG, Wilson FH, Canessa CM, Lifton RP, Hebert SC. WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1). The Journal Of Physiology 2006, 571: 275-286. PMID: 16357011, PMCID: PMC1796803, DOI: 10.1113/jphysiol.2005.102202.Peer-Reviewed Original ResearchConceptsDistal convoluted tubuleInhibition of ROMK1KCNQ1/KCNE1Renal NaCl reabsorptionEpithelial sodium channelAmiloride-sensitive currentDistal nephronVivo effectsConvoluted tubulesKinase-dependent activationQT syndromeNCC activityNaCl reabsorptionNephron segmentsDuct principal cellsHereditary hypertensionSodium channelsPrincipal cellsII cellsRenal NaClSurface expressionXenopus laevis oocytesHypertensionHomeostatic systemDisease
2005
WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis
Rinehart J, Kahle KT, de los Heros P, Vazquez N, Meade P, Wilson FH, Hebert SC, Gimenez I, Gamba G, Lifton RP. WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2005, 102: 16777-16782. PMID: 16275913, PMCID: PMC1283841, DOI: 10.1073/pnas.0508303102.Peer-Reviewed Original ResearchConceptsEffects of WNK3Kinase-inactive stateSerine-threonine kinaseWNK kinase familyActivation of NKCC2Kinase familyPositive regulatorThr-189Potent inhibitorPlasma membraneRelated membersThr-184Coexpression studiesMolecular switchNKCC2 phosphorylationFunction mutationsNormal blood pressure homeostasisWNK3Intercellular junctionsBlood pressure homeostasisRenal epitheliumPotent activatorRenal NaCl reabsorptionTransportersHomeostasisRegulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch
Kahle KT, Wilson FH, Lifton RP. Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch. Trends In Endocrinology And Metabolism 2005, 16: 98-103. PMID: 15808806, DOI: 10.1016/j.tem.2005.02.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiochemistryHumansIon TransportIonsMolecular BiologyProtein Serine-Threonine KinasesConceptsWNK kinasesSerine-threonine kinaseNovel molecular switchSubstitution of cysteinePhysiological regulatory pathwaysRecent physiological workMolecular genetic studiesCatalytic domainSubdomain IIRegulatory pathwaysIon flux pathwaysMolecular switchWNK4 kinaseKinasePhysiological workBasolateral membranePathwayIon transport pathwaysTransport pathwaysWNK4Electrolyte homeostasisProminent roleSyndrome of hypertensionWNK1Key component
2004
Paracellular Cl- permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension
Kahle KT, MacGregor GG, Wilson FH, Van Hoek AN, Brown D, Ardito T, Kashgarian M, Giebisch G, Hebert SC, Boulpaep EL, Lifton RP. Paracellular Cl- permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 14877-14882. PMID: 15465913, PMCID: PMC522037, DOI: 10.1073/pnas.0406172101.Peer-Reviewed Original ResearchConceptsPseudohypoaldosteronism type IIPHAII-mutant WNK4Paracellular fluxPotent antihypertensive agentTight junction proteinsTight junctionsAntihypertensive agentsParacellular ion fluxPharmacologic propertiesTight junction structureTranscellular transportersWild-type WNK4Normal physiologyHypertensionTransepithelial resistanceWNK signalingKidney epitheliumTight junction formationParacellular pathwayWNK4Effect of WNK4EpitheliumType IIWNK4 kinaseHomeostasisWNK kinases: molecular regulators of integrated epithelial ion transport
Kahle KT, Wilson FH, Lalioti M, Toka H, Qin H, Lifton RP. WNK kinases: molecular regulators of integrated epithelial ion transport. Current Opinion In Nephrology & Hypertension 2004, 13: 557-562. PMID: 15300163, DOI: 10.1097/00041552-200409000-00012.Peer-Reviewed Original ResearchMeSH KeywordsEpitheliumHumansIon TransportKidneyPoint MutationProtein Serine-Threonine KinasesPseudohypoaldosteronismSignal TransductionConceptsPseudohypoaldosteronism type IIWNK kinasesPotassium ion channelsChloride ion fluxIon channelsSerine-threonine kinaseCoordinated regulationDiverse epitheliaMolecular regulatorsMolecular switchKinasePotassium ion secretionDynamic regulatorGeneral roleDisease physiologyIon fluxIntegrated regulationElectrolyte homeostasisEpithelial ion transportEpithelial transportersEssential roleWNK4HomeostasisFlux pathwaysMutationsWNK4 regulates apical and basolateral Cl– flux in extrarenal epithelia
Kahle KT, Gimenez I, Hassan H, Wilson FH, Wong RD, Forbush B, Aronson PS, Lifton RP. WNK4 regulates apical and basolateral Cl– flux in extrarenal epithelia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2004, 101: 2064-2069. PMID: 14769928, PMCID: PMC357052, DOI: 10.1073/pnas.0308434100.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCarrier ProteinsCell PolarityChloridesEpitheliumHumansImmunohistochemistryIon TransportKidneyMembrane ProteinsMembrane Transport ProteinsMiceOocytesProtein Serine-Threonine KinasesRNA, MessengerSodium-Potassium-Chloride SymportersSolute Carrier Family 12, Member 2Sulfate TransportersXenopus laevisConceptsCl fluxBlood-brain barrierUnrelated ion channelsActivity of mediatorsWNK4 mRNABile ductPancreatic ductExtrarenal expressionExtrarenal tissuesCl(-) handlingPseudohypoaldosteronism type IIChannel ROMKNaCl reabsorptionSerine-threonine kinase WNK4Specialized endotheliumExchanger SLC26A6NaCl cotransporterWNK4 effectsColonic cryptsEpitheliumVariable inhibitionSweat ductsTight junctionsKidneyElectrolyte flux
2003
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion
Kahle KT, Wilson FH, Leng Q, Lalioti MD, O'Connell AD, Dong K, Rapson AK, MacGregor GG, Giebisch G, Hebert SC, Lifton RP. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nature Genetics 2003, 35: 372-376. PMID: 14608358, DOI: 10.1038/ng1271.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsClathrinEndocytosisGreen Fluorescent ProteinsIon TransportKidneyLuminescent ProteinsMicePotassiumPotassium ChannelsPotassium Channels, Inwardly RectifyingProtein Serine-Threonine KinasesPseudohypoaldosteronismRatsReceptors, DrugSodium ChlorideSodium Chloride SymportersSolute Carrier Family 12, Member 3SymportersXenopus laevisConceptsDiverse ion transportersClathrin-dependent endocytosisSerine-threonine kinase WNK4WNK4 kinase activityRenal Na-Cl cotransporterDiverse physiologic processesRenal NaClWild-type WNK4Positional cloningMultifunctional regulatorXenopus laevis oocytesInhibition of ROMKIon transportersKinase activityGenetic analysisSystems biologyMolecular switchNa-Cl cotransporterWNK4's inhibitionLaevis oocytesChannel ROMKWNK4Renal NaCl reabsorptionMutationsSame mutationWNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl−-transporting epithelia
Choate KA, Kahle KT, Wilson FH, Nelson-Williams C, Lifton RP. WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl−-transporting epithelia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2003, 100: 663-668. PMID: 12522152, PMCID: PMC141053, DOI: 10.1073/pnas.242728499.Peer-Reviewed Original ResearchConceptsPseudohypoaldosteronism type IIPancreatic ductCl fluxRenal tubular acidosisSweat ductsAutosomal dominant disorderBile ductBiliary ductsTubular acidosisExtrarenal tissuesDistal nephronCl reabsorptionEsophageal epitheliumCystic fibrosisWNK4 expressionColonic cryptsEpitheliumDominant disorderSelective modulationHypertensionHyperkalemiaBasal layerGallbladderDuctKidneyMolecular pathogenesis of inherited hypertension with hyperkalemia: The Na–Cl cotransporter is inhibited by wild-type but not mutant WNK4
Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP. Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na–Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proceedings Of The National Academy Of Sciences Of The United States Of America 2003, 100: 680-684. PMID: 12515852, PMCID: PMC141056, DOI: 10.1073/pnas.242735399.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceFemaleHyperkalemiaHypertensionIon TransportMiceMolecular Sequence DataProtein Serine-Threonine KinasesSodiumSodium Chloride SymportersSymportersXenopus laevisXenopus ProteinsConceptsNa-Cl cotransporterPseudohypoaldosteronism type IIMutant WNK4Molecular pathogenesisThiazide-sensitive Na-Cl cotransporterSerine-threonine kinases WNK1Forms of hypertensionMembrane expressionMissense mutationsMetabolic acidosisT cellsDistal nephronPHAII phenotypesHypertensionNa influxHEK 293T cellsSurface expressionWNK signalingHyperkalemiaFunction mutationsPathogenesisCotransporterWNK4
2001
Human Hypertension Caused by Mutations in WNK Kinases
Wilson F, Disse-Nicodème S, Choate K, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford D, Lipkin G, Achard J, Feely M, Dussol B, Berland Y, Unwin R, Mayan H, Simon D, Farfel Z, Jeunemaitre X, Lifton R. Human Hypertension Caused by Mutations in WNK Kinases. Science 2001, 293: 1107-1112. PMID: 11498583, DOI: 10.1126/science.1062844.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBase SequenceChromosome MappingChromosomes, Human, Pair 12Chromosomes, Human, Pair 17CytoplasmFemaleGene Expression Regulation, EnzymologicGenetic LinkageHumansHypertensionIntercellular JunctionsIntracellular Signaling Peptides and ProteinsIntronsKidney Tubules, CollectingKidney Tubules, DistalMaleMembrane ProteinsMicroscopy, FluorescenceMinor Histocompatibility AntigensMolecular Sequence DataMutationMutation, MissensePedigreePhosphoproteinsProtein Serine-Threonine KinasesPseudohypoaldosteronismSequence DeletionSignal TransductionWNK Lysine-Deficient Protein Kinase 1Zonula Occludens-1 ProteinConceptsMajor public health problemPublic health problemRenal salt reabsorptionAntihypertensive drugsHuman hypertensionUnknown causeDistal nephronKidney segmentsPseudohypoaldosteronism type IIHealth problemsSalt reabsorptionHypertensionWNK1 expressionNew targetsWNK kinasesTight junctionsType IISerine-threonine kinaseIntronic deletionWNK4WNK familyMutationsWNK1KinaseExcretion