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 ResearchConceptsPseudohypoaldosteronism 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 ResearchConceptsIntravascular 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
2004
WNK4 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 mutationMolecular 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 ResearchConceptsNa-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