2017
Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD
Bushinsky DA, Hostetter T, Klaerner G, Stasiv Y, Lockey C, McNulty S, Lee A, Parsell D, Mathur V, Li E, Buysse J, Alpern R. Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD. Clinical Journal Of The American Society Of Nephrology 2017, 13: 26-35. PMID: 29102959, PMCID: PMC5753317, DOI: 10.2215/cjn.07300717.Peer-Reviewed Original ResearchConceptsSerum bicarbonateEnd of treatmentMetabolic acidosisTreatment groupsBaseline serum bicarbonateMean baseline eGFRMEq/LSignificant adverse effectsBaseline eGFRGastrointestinal eventsAdverse eventsFirst doseControlled TrialsHeart failurePatientsCKDBaseline levelsMean increaseAbstractTextUnit studiesAcidosisAdverse effectsPlaceboTreatmentDays
2010
Acid regulation of NaDC-1 requires a functional endothelin B receptor
Liu L, Zacchia M, Tian X, Wan L, Sakamoto A, Yanagisawa M, Alpern RJ, Preisig PA. Acid regulation of NaDC-1 requires a functional endothelin B receptor. Kidney International 2010, 78: 895-904. PMID: 20703215, DOI: 10.1038/ki.2010.264.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisAnimalsBiological TransportCell LineDicarboxylic Acid TransportersDisease Models, AnimalEndothelin B Receptor AntagonistsEndothelin-1Hydrogen-Ion ConcentrationKidneyMiceMice, KnockoutMicrovilliOligopeptidesOpossumsOrganic Anion Transporters, Sodium-DependentPiperidinesProtein Structure, TertiaryReceptor, Endothelin AReceptor, Endothelin BRecombinant Fusion ProteinsSignal TransductionSymportersTime FactorsTransfectionConceptsEndothelin-1Endothelin-B receptor antagonistFunctional endothelin B receptorsStimulatory effectAcid-stimulatory effectET-1 effectsB receptor antagonistNHE3 activityEndothelin B receptorWild-type miceET-1 stimulationMajor physiological stimulusNaDC-1Acid ingestionReceptor antagonistCitrate reabsorptionReceptor expressionCitrate excretionOpossum kidneyAcid loadB receptorAcid feedingPhysiological stimuliStimulationMice
2004
An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3
Licht C, Laghmani K, Yanagisawa M, Preisig PA, Alpern RJ. An autocrine role for endothelin-1 in the regulation of proximal tubule NHE3. Kidney International 2004, 65: 1320-1326. PMID: 15086471, DOI: 10.1111/j.1523-1755.2004.00506.x.Peer-Reviewed Original ResearchConceptsChronic metabolic acidosisMetabolic acidosisReverse transcription-polymerase chain reactionProximal tubulesKidney cortexCompetitive reverse transcription-polymerase chain reactionProximal tubule NHE3NHE3 activityPreproET-1 expressionEndothelin B receptorEndothelin-1 expressionET-1 expressionPreproET-1 mRNA abundancePreproET-1 mRNA expressionTranscription-polymerase chain reactionProximal tubule cellsRenal proximal tubulesMRNA abundanceEndothelin-1Control ratsAbdominal aortaAutocrine roleAcidosisTubule cellsAutocrine regulationDietary acid, endothelins, and sleep.
Alpern RJ, Preisig PA. Dietary acid, endothelins, and sleep. Transactions Of The American Clinical And Climatological Association 2004, 115: 385-93; discussion 393-4. PMID: 17060981, PMCID: PMC2263788.Peer-Reviewed Original ResearchConceptsTrafficking of NHE3Proximal tubule cell lineNHE3 activityTubule cell lineSecond intracellular loopEndothelin expressionDietary acidNHE3 abundanceActivation of NHE3OKP cellsProximal tubulesNHE3 mRNAApical membraneHomeostatic responseProtein expressionC-fosReceptor specificityIntracellular loopReceptorsEndothelinCell linesC-JunNHE3C-SrcAcid signaling
2002
Bicarbonate reabsorption and NHE-3 expression: Abundance and activity are increased in Henle's loop of remnant rats
Capasso G, Rizzo M, Pica A, Di Maio FS, Moe OW, Alpern RJ, De Santo NG. Bicarbonate reabsorption and NHE-3 expression: Abundance and activity are increased in Henle's loop of remnant rats. Kidney International 2002, 62: 2126-2135. PMID: 12427137, DOI: 10.1046/j.1523-1755.2002.00681.x.Peer-Reviewed Original ResearchRole of c-SRC and ERK in acid-induced activation of NHE3
Tsuganezawa H, Sato S, Yamaji Y, Preisig PA, Moe OW, Alpern RJ. Role of c-SRC and ERK in acid-induced activation of NHE3. Kidney International 2002, 62: 41-50. PMID: 12081562, DOI: 10.1046/j.1523-1755.2002.00418.x.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisAmmonium ChlorideAnimalsCells, CulturedCSK Tyrosine-Protein KinaseEnzyme ActivationJNK Mitogen-Activated Protein KinasesMaleMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein KinasesPhosphorylationProtein Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene Proteins c-fosRatsRats, Sprague-DawleySodium-Hydrogen Exchanger 3Sodium-Hydrogen ExchangersSrc-Family KinasesConceptsOKP cellsAcid-induced activationNHE3 activityERK/c-fosC-fos expressionC-Fos activationCytoplasmic pH (pHi) recoveryC-SrcRenal proximal tubulesAcid incubationActivation of NHE3Renal epithelial cellsCultured renal epithelial cellsProximal tubulesChronic acidosisInhibition of MEKNHE3 activationInhibited activationNormal levelsAcid loadImmune complex kinase assayERK kinaseAcidosisPH recoveryEpithelial cellsThe role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis.
Laghmani K, Preisig PA, Alpern RJ. The role of endothelin in proximal tubule proton secretion and the adaptation to a chronic metabolic acidosis. Journal Of Nephrology 2002, 15 Suppl 5: s75-87. PMID: 12027224.Peer-Reviewed Original ResearchConceptsProximal tubulesMetabolic acidosisEndothelin-1NHE3 activityRole of endothelinImmediate early gene c-fosEndothelin B receptorEarly gene c-fosChronic metabolic acidosisGene c-fosKidney functionActivation of Pyk2Endothelin effectsApical membrane NHE3NHE3 abundanceB receptorEndothelinApical membraneAcidosisSecretionEffector agentsC-fosTubulesProton secretionC-Jun
2001
Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis
Laghmani K, Preisig P, Moe O, Yanagisawa M, Alpern R. Endothelin-1/endothelin-B receptor–mediated increases in NHE3 activity in chronic metabolic acidosis. Journal Of Clinical Investigation 2001, 107: 1563-1569. PMID: 11413164, PMCID: PMC200190, DOI: 10.1172/jci11234.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisAmmoniaAnimalsBicarbonatesChronic DiseaseCitric AcidCulture TechniquesEndothelin-1EndothelinsKidney Tubules, ProximalMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicProtein PrecursorsReceptor, Endothelin BReceptors, EndothelinRNA, MessengerSodiumSodium-Hydrogen Exchanger 3Sodium-Hydrogen ExchangersConceptsTg/tgAcid ingestionTitratable acid excretionMetabolic acidosisNHE3 activityAcid excretionReceptor-deficient miceEndothelin B receptorET-1 expressionChronic metabolic acidosisProximal tubule suspensionsAmmonium excretionM endothelinNa/H antiporterC57BL/6 miceApical membrane NHE3Renal epithelial cellsCultured renal epithelial cellsEndothelin-1/Tubule suspensionsMRNA expressionControl dietMiceExcretionEpithelial cells
2000
Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney
Aruga S, Wehrli S, Kaissling B, Moe O, Preisig P, Pajor A, Alpern R. Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney. Kidney International 2000, 58: 206-215. PMID: 10886565, DOI: 10.1046/j.1523-1755.2000.00155.x.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisAcidsAcute DiseaseAlkaliesAmmonium ChlorideAnimalsCarrier ProteinsChronic DiseaseCitratesDicarboxylic Acid TransportersGene ExpressionKidney CortexKidney Tubules, ProximalMaleMembrane ProteinsOrganic Anion Transporters, Sodium-DependentRatsRats, Sprague-DawleyRNA, MessengerSodium BicarbonateSymporters
1999
Role of glucocorticoids in acidosis
Hamm L, Ambühl P, Alpern R. Role of glucocorticoids in acidosis. American Journal Of Kidney Diseases 1999, 34: 960-965. PMID: 10561158, DOI: 10.1016/s0272-6386(99)70059-4.Peer-Reviewed Original Research
1998
Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia
Melnick J, Preisig P, Haynes S, Pak C, Sakhaee K, Alpern R. Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia. Kidney International 1998, 54: 1670-1674. PMID: 9844143, DOI: 10.1046/j.1523-1755.1998.00150.x.Peer-Reviewed Original ResearchConceptsUrinary citrate excretionCitrate excretionUrinary citrateMetabolic acidosisATP-citrate lyaseEffects of enalaprilRenal citrate metabolismUrine citrate concentrationRenal cortical tissueChronic metabolic acidosisProximal tubular cellsPlasma pHNa/H antiporterAngiotensin IIIntracellular acidosisEnalaprilTubular cellsCitrate lyaseHypokalemiaEnzyme inhibitorsATP citrate lyase activityAcidosisCortical tissueRatsCitrate metabolismRenal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia
Melnick J, Preisig P, Moe O, Srere P, Alpern R. Renal cortical mitochondrial aconitase is regulated in hypo- and hypercitraturia. Kidney International 1998, 54: 160-165. PMID: 9648074, DOI: 10.1046/j.1523-1755.1998.00974.x.Peer-Reviewed Original Research
1997
Intracellular acidosis activates c-Src
Yamaji Y, Tsuganezawa H, Moe OW, Alpern RJ. Intracellular acidosis activates c-Src. American Journal Of Physiology 1997, 272: c886-c893. PMID: 9124524, DOI: 10.1152/ajpcell.1997.272.3.c886.Peer-Reviewed Original ResearchConceptsC-SrcC-Src activationProtein tyrosine phosphatase inhibitorProtein tyrosine kinase pathwaysMedium acidificationTyrosine phosphatase inhibitorProtein tyrosine phosphorylationC-Src activityTyrosine kinase pathwayPhosphatase inhibitorPhosphotyrosine contentCell pH changesTyrosine phosphorylationCytosolic proteinsKinase pathwayRenal proximal tubule cell lineCellular responsesSodium orthovanadateNovel mechanismProximal tubule cell lineCell linesTubule cell lineCell acidificationSignificant activationActivationThe clinical spectrum of chronic metabolic acidosis: Homeostatic mechanisms produce significant morbidity
Alpern R, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: Homeostatic mechanisms produce significant morbidity. American Journal Of Kidney Diseases 1997, 29: 291-302. PMID: 9016905, DOI: 10.1016/s0272-6386(97)90045-7.Peer-Reviewed Original ResearchConceptsChronic metabolic acidosisMetabolic acidosisHomeostatic responseSerum HCO3Acid loadBody's homeostatic responseHomeostatic mechanismsMuscle protein breakdownNormal homeostatic mechanismsSignificant morbidityClinical spectrumMeat ingestionBone demineralizationRenal growthClinical conditionsPathologic processesPathologic consequencesAcidosisProtein breakdownBloodResponseMorbidityPatientsNephrolithiasisIngestionChronic metabolic acidosis enhances NHE-3 protein abundance and transport activity in the rat thick ascending limb by increasing NHE-3 mRNA.
Laghmani K, Borensztein P, Ambühl P, Froissart M, Bichara M, Moe OW, Alpern RJ, Paillard M. Chronic metabolic acidosis enhances NHE-3 protein abundance and transport activity in the rat thick ascending limb by increasing NHE-3 mRNA. Journal Of Clinical Investigation 1997, 99: 24-30. PMID: 9011571, PMCID: PMC507763, DOI: 10.1172/jci119128.Peer-Reviewed Original Research
1996
Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney
Ambuhl P, Amemiya M, Danczkay M, Lotscher M, Kaissling B, Moe OW, Preisig PA, Alpern RJ. Chronic metabolic acidosis increases NHE3 protein abundance in rat kidney. American Journal Of Physiology 1996, 271: f917-f925. PMID: 8898023, DOI: 10.1152/ajprenal.1996.271.4.f917.Peer-Reviewed Original ResearchConceptsNHE3 protein abundanceChronic metabolic acidosisNHE3 mRNA abundanceMetabolic acidosisThick ascending limbProximal tubulesAscending limbNa/H antiporter activityAcidosis-induced increaseMRNA abundanceNa/H antiporterNHE3 abundanceProtein abundanceAcidosisRat kidneyWestern blotS2 segmentsH antiporterRatsNHE3 isoformPresent studyLimbTubules
1994
Acid activation of immediate early genes in renal epithelial cells.
Yamaji Y, Moe OW, Miller RT, Alpern RJ. Acid activation of immediate early genes in renal epithelial cells. Journal Of Clinical Investigation 1994, 94: 1297-1303. PMID: 8083371, PMCID: PMC295215, DOI: 10.1172/jci117448.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAcidosisAnimalsCell LineCell NucleusDNA-Binding ProteinsEarly Growth Response Protein 1EpitheliumGene Expression RegulationGenes, Immediate-EarlyHydrogen-Ion ConcentrationImmediate-Early ProteinsIonomycinKidney Tubules, ProximalMiceProto-Oncogene Proteins c-fosProto-Oncogene Proteins c-junRNA, MessengerTetradecanoylphorbol AcetateTranscription FactorsTranscriptional ActivationConceptsTyrosine kinase pathwayGene activationKinase pathwayMouse proximal tubule cell lineC-JunRate of transcriptionProtein kinase CImmediate early genesRenal epithelial cellsMRNA speciesPretreatment of cellsGene expressionKinase CEarly genesGenesMRNA abundanceProximal tubule cell lineCell linesTubule cell lineRenal tubule cellsEpithelial cellsC-fosGrowth factorCellsMRNA
1992
Induction of stress proteins in cultured myogenic cells. Molecular signals for the activation of heat shock transcription factor during ischemia.
Benjamin IJ, Horie S, Greenberg ML, Alpern RJ, Williams RS. Induction of stress proteins in cultured myogenic cells. Molecular signals for the activation of heat shock transcription factor during ischemia. Journal Of Clinical Investigation 1992, 89: 1685-1689. PMID: 1569208, PMCID: PMC443048, DOI: 10.1172/jci115768.Peer-Reviewed Original ResearchConceptsGlucose deprivationControl levelsATP depletionHeat shock protein 70Ischemic injuryHeat shock factorIschemic tissueIschemic cellsHigh-pressure liquid chromatographyHypoxia resultsM rotenoneC2 myogenic cellsStress proteinsMyogenic cellsNormoxic conditionsOxidative metabolismProtein 70ATP storesCultured myogenic cellsConsensus heat shock elementIschemiaATP poolHSF activationMajor stress proteinsDNA-binding activity
1991
Differential regulation of Na/H antiporter by acid in renal epithelial cells and fibroblasts.
Moe OW, Miller RT, Horie S, Cano A, Preisig PA, Alpern RJ. Differential regulation of Na/H antiporter by acid in renal epithelial cells and fibroblasts. Journal Of Clinical Investigation 1991, 88: 1703-1708. PMID: 1658050, PMCID: PMC295708, DOI: 10.1172/jci115487.Peer-Reviewed Original ResearchConceptsNa/H antiporter activityRenal tubule cellsNa/H antiporterMCT cellsRenal epithelial cellsTubule cellsCell linesCultured renal tubule cellsEpithelial cellsMRNA abundanceOpossum kidney cell lineChronic metabolic acidosisAcid preincubationTubule cell lineRat renal cortexH antiporterAntiporter activityUnderlying molecular mechanismsDifferential regulationMetabolic acidosisRenal cortexAcidotic environmentAcid feedingAdaptive increaseKidney cell line
1985
A model of proximal tubular bicarbonate absorption
Alpern RJ, Rector FC. A model of proximal tubular bicarbonate absorption. American Journal Of Physiology 1985, 248: f272-f281. PMID: 3970216, DOI: 10.1152/ajprenal.1985.248.2.f272.Peer-Reviewed Original Research