2024
Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease
Zhang C, Rehman M, Tian X, Pei S, Gu J, Bell T, Dong K, Tham M, Cai Y, Wei Z, Behrens F, Jetten A, Zhao H, Lek M, Somlo S. Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease. Nature Communications 2024, 15: 3698. PMID: 38693102, PMCID: PMC11063051, DOI: 10.1038/s41467-024-48025-6.Peer-Reviewed Original ResearchConceptsMouse models of autosomal dominant polycystic kidney diseaseModel of autosomal dominant polycystic kidney diseasePolycystin signalingAutosomal dominant polycystic kidney diseasePolycystin-1Polycystic kidney diseaseTreat autosomal dominant polycystic kidney diseaseGlis2Primary ciliaKidney tubule cellsSignaling pathwayMouse modelDominant polycystic kidney diseasePotential therapeutic targetTranslatomeAntisense oligonucleotidesKidney diseasePolycystinMouse kidneyFunctional effectorsCyst formationTherapeutic targetInactivationFunctional targetPharmacological targets
2021
Restoration of proximal tubule flow-activated transport prevents cyst growth in polycystic kidney disease
Du Z, Tian X, Ma M, Somlo S, Weinstein AM, Wang T. Restoration of proximal tubule flow-activated transport prevents cyst growth in polycystic kidney disease. JCI Insight 2021, 6: e146041. PMID: 33886508, PMCID: PMC8262298, DOI: 10.1172/jci.insight.146041.Peer-Reviewed Original ResearchConceptsGlomerular filtration rateGlomerulotubular balanceRenal cyst formationCyst formationReceptor 1 antagonistPolycystic kidney diseaseKidney weightUntreated miceDA1 antagonistControl miceKidney diseaseFiltration rateFractional reabsorptionCystic indexMouse modelCyst growthConditional KOHCO3- absorptionHeterozygous miceSame antagonistsMicePT transportAntagonistEpithelial ciliaHCO3- transport
2020
Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease
Zhang C, Balbo B, Ma M, Zhao J, Tian X, Kluger Y, Somlo S. Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2020, 32: 41-51. PMID: 33046531, PMCID: PMC7894654, DOI: 10.1681/asn.2020040511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCatalytic DomainCDC2 Protein KinaseCell ProliferationCrosses, GeneticDNA ReplicationExome SequencingFemaleGene Expression ProfilingGene Expression RegulationMaleMiceMice, Inbred C57BLMice, KnockoutMutationPhenotypePolycystic Kidney, Autosomal DominantPyruvate Dehydrogenase Acetyl-Transferring KinaseRNA-SeqTranscription, GeneticTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseaseCyst cell proliferationPolycystic kidney diseaseKidney diseaseADPKD progressionCell proliferationModel of ADPKDCyst growthProgression of ADPKDDominant polycystic kidney diseaseDouble knockout miceCandidate pathwaysKidney functionCyst progressionMouse modelUnbiased transcriptional profilingProgressionCellular mechanismsKinase 1 activityCystic phenotypeSelective targetingKidneyConditional inactivationDouble knockoutProliferation
2018
Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease
Cassini MF, Kakade VR, Kurtz E, Sulkowski P, Glazer P, Torres R, Somlo S, Cantley LG. Mcp1 Promotes Macrophage-Dependent Cyst Expansion in Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2018, 29: 2471-2481. PMID: 30209078, PMCID: PMC6171277, DOI: 10.1681/asn.2018050518.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseSingle knockout miceTubular cell injuryDominant polycystic kidney diseaseCyst growthPolycystic kidney diseaseKidney diseaseCell injuryMonocyte chemoattractant protein-1Alternative activation phenotypeChemoattractant protein-1Double knockout miceOrthologous mouse modelCell proliferative rateRenal functionMacrophage accumulationMacrophage infiltrationReceptor CCR2Cystic dilationMacrophage numbersFunctional improvementOxidative DNA damageMouse modelActivation phenotypeCyst expansionPolycystin-2-dependent control of cardiomyocyte autophagy
Criollo A, Altamirano F, Pedrozo Z, Schiattarella GG, Li DL, Rivera-Mejías P, Sotomayor-Flores C, Parra V, Villalobos E, Battiprolu PK, Jiang N, May HI, Morselli E, Somlo S, de Smedt H, Gillette TG, Lavandero S, Hill JA. Polycystin-2-dependent control of cardiomyocyte autophagy. Journal Of Molecular And Cellular Cardiology 2018, 118: 110-121. PMID: 29518398, DOI: 10.1016/j.yjmcc.2018.03.002.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseIntracellular CaCardiomyocyte autophagyAutophagic fluxBAPTA-AMDominant polycystic kidney diseaseStress-induced autophagySarcoplasmic reticulum CaPolycystic kidney diseasePolycystin-2Impaired autophagic fluxKidney diseaseKnockout miceConsiderable evidence pointsMTOR inhibitionReticulum CaExtracellular CaMultiple cell typesAutophagic activityAutophagy inductionHomeostasisAutophagyEvidence pointsAutophagic controlCell typesGlutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease
Soomro I, Sun Y, Li Z, Diggs L, Hatzivassiliou G, Thomas AG, Rais R, Parker SJ, Slusher BS, Kimmelman AC, Somlo S, Skolnik EY. Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. Nephrology Dialysis Transplantation 2018, 33: 1343-1353. PMID: 29420817, PMCID: PMC6070111, DOI: 10.1093/ndt/gfx349.Peer-Reviewed Original ResearchConceptsCyst growthCB-839Mouse modelGlutaminase 1Glutamine metabolismAutosomal dominant polycystic kidney disease cellsAutosomal dominant polycystic kidney diseaseCyst-lining epithelial cellsNormal human kidneyCompensatory metabolic changesInhibited mammalian targetPolycystic kidney diseaseCyst-lining epitheliaTumor cell proliferationKidney diseaseAnimal modelsGLS1 inhibitionHuman ADPKD kidneysHuman kidneyMammalian targetVariable outcomesCyst formationMetabolic changesADPKDMetabolism of glutamineGanetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD)
Nikonova AS, Deneka AY, Kiseleva AA, Korobeynikov V, Gaponova A, Serebriiskii IG, Kopp MC, Hensley HH, Seeger‐Nukpezah T, Somlo S, Proia DA, Golemis EA. Ganetespib limits ciliation and cystogenesis in autosomal‐dominant polycystic kidney disease (ADPKD). The FASEB Journal 2018, 32: 2735-2746. PMID: 29401581, PMCID: PMC5901382, DOI: 10.1096/fj.201700909r.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseEnd-stage renal diseaseLoss of Pkd1Conditional mouse modelHeat shock protein-90 clientsRenal diseaseKidney enlargementClinical Hsp90 inhibitorsRenal cystsAmeliorated symptomsMouse modelNew biologic activityCiliary lossCystic growthDiseaseBiologic activityGlycolysis inhibitorGanetespibADPKD pathogenesisVivo lossHsp90 inhibitorsHsp90 inhibitionRenal cilia
2017
Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease
Wang Q, Cobo-Stark P, Patel V, Somlo S, Han PL, Igarashi P. Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease. Kidney International 2017, 93: 403-415. PMID: 29042084, PMCID: PMC5794572, DOI: 10.1016/j.kint.2017.08.005.Peer-Reviewed Original ResearchConceptsPolycystic kidney diseaseOrthologous mouse modelSingle mutant miceMutant miceRenal epithelial cellsCyst growthCAMP levelsKidney diseaseEpithelial cellsMouse modelTreatment of PKDA-kinase anchoring protein 150Renal cyclic AMPKidneys of miceCyclic AMPDouble mutant miceRenal cAMP levelsInhibition of AC5Kidney injuryLevels of cAMPPrimary ciliaKidney enlargementKidney functionCyst indexMice
2016
Double inhibition of cAMP and mTOR signalling may potentiate the reduction of cell growth in ADPKD cells
de Stephanis L, Bonon A, Varani K, Lanza G, Gafà R, Pinton P, Pema M, Somlo S, Boletta A, Aguiari G. Double inhibition of cAMP and mTOR signalling may potentiate the reduction of cell growth in ADPKD cells. Clinical And Experimental Nephrology 2016, 21: 203-211. PMID: 27278932, PMCID: PMC5496448, DOI: 10.1007/s10157-016-1289-1.Peer-Reviewed Original ResearchMeSH KeywordsAdenosineAdenosine A3 Receptor AgonistsAnimalsCell LineCell ProliferationCREB-Binding ProteinCyclic AMPDisease Models, AnimalDrug SynergismDrug Therapy, CombinationExtracellular Signal-Regulated MAP KinasesGenetic Predisposition to DiseaseHumansKidneyMice, Inbred C57BLMice, KnockoutPhenotypePhosphorylationPolycystic Kidney, Autosomal DominantProtein Kinase InhibitorsSignal TransductionSirolimusTime FactorsTOR Serine-Threonine KinasesTRPP Cation ChannelsConceptsCl-IBADPKD patientsCell proliferationADPKD cellsActivation of A3ARCell growthAgonist Cl-IBPolycystin-1MethodsThe inhibitionCombined sequential treatmentRenal functionKidney weightAbnormal cell proliferationERK kinase activityRenal pathologyA3 receptorsInhibition of CREBKidney tissueKinase activityPolycystin-2Marked reductionDirect cell countingKidney cystsMutations of PKD1ERK phosphorylation
2015
Human Polycystin-2 Transgene Dose-Dependently Rescues ADPKD Phenotypes in Pkd2 Mutant Mice
Li A, Tian X, Zhang X, Huang S, Ma Y, Wu D, Moeckel G, Somlo S, Wu G. Human Polycystin-2 Transgene Dose-Dependently Rescues ADPKD Phenotypes in Pkd2 Mutant Mice. American Journal Of Pathology 2015, 185: 2843-2860. PMID: 26435415, PMCID: PMC4607765, DOI: 10.1016/j.ajpath.2015.06.014.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseMouse modelADPKD phenotypeSevere cystic phenotypeWild-type miceDose-dependent mannerPolycystic kidney diseaseForms of ADPKDKidney diseasePancreatic cystsEffective treatmentFunctional restorationMutant miceTransgene doseMiceCyst formationReduced proliferationEpithelial cellsCystic phenotypeKidneyLiverFurther ameliorationPC2 activityPhenotypeMolecular genetic mechanismsPolycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability
Pedrozo Z, Criollo A, Battiprolu PK, Morales CR, Contreras-Ferrat A, Fernández C, Jiang N, Luo X, Caplan MJ, Somlo S, Rothermel BA, Gillette TG, Lavandero S, Hill JA. Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability. Circulation 2015, 131: 2131-2142. PMID: 25888683, PMCID: PMC4470854, DOI: 10.1161/circulationaha.114.013537.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBiomarkersCalcium Channels, L-TypeCardiomegalyCells, CulturedFibrosisHypertrophyHypotonic SolutionsMaleMechanotransduction, CellularMiceMice, KnockoutMyocytes, CardiacProtein Interaction MappingProtein StabilityProtein Structure, TertiaryRatsRats, Sprague-DawleyRecombinant Fusion ProteinsRNA InterferenceStress, MechanicalTRPP Cation ChannelsConceptsL-type calcium channel activityCalcium channel activityNeonatal rat ventricular myocytesRat ventricular myocytesKnockout miceVentricular myocytesChannel activityMechanical stretchNeonatal rat ventricular myocyte hypertrophyProtein levelsVentricular myocyte hypertrophyL-type Ca2G protein-coupled receptor-like proteinPolycystin-1Channel protein levelsCyclic mechanical stretchControl miceInterstitial fibrosisStress-induced activationCardiac massMechanical stress-induced activationCardiac functionRNAi-dependent knockdownCardiac hypertrophyLittermate controlsSec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
Fedeles SV, So JS, Shrikhande A, Lee SH, Gallagher AR, Barkauskas CE, Somlo S, Lee AH. Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity. Journal Of Clinical Investigation 2015, 125: 1955-1967. PMID: 25844898, PMCID: PMC4463201, DOI: 10.1172/jci78863.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineDisease Models, AnimalDNA HelicasesDNA-Binding ProteinsEndoribonucleasesFemaleGlucosidasesIntracellular Signaling Peptides and ProteinsKidneyMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMolecular ChaperonesPolycystic Kidney, Autosomal DominantPolycystic Kidney, Autosomal RecessiveProtein Serine-Threonine KinasesProtein Structure, TertiaryReceptors, G-Protein-CoupledRecombinant Fusion ProteinsRegulatory Factor X Transcription FactorsRNA SplicingRNA, Small InterferingRNA-Binding ProteinsTranscription FactorsTransfectionTRPP Cation ChannelsUnfolded Protein ResponseX-Box Binding Protein 1ConceptsG protein-coupled receptor proteolysis siteCyst formationPolycystic liver diseaseGPS cleavagePolycystin-1IRE1α-XBP1 branchMurine genetic modelsPolycystic kidney phenotypeLiver diseasePolycystic diseaseCystic diseaseDisease manifestationsMurine modelDisease severityKidney phenotypeXBP1 activationUnfolded protein response pathwayDiseaseXBP1 overexpressionPC1 functionsProtein response pathwayEnforced expressionMiceXBP1Activation of XBP1
2014
N-Glycosylation Determines the Abundance of the Transient Receptor Potential Channel TRPP2*
Hofherr A, Wagner C, Fedeles S, Somlo S, Köttgen M. N-Glycosylation Determines the Abundance of the Transient Receptor Potential Channel TRPP2*. Journal Of Biological Chemistry 2014, 289: 14854-14867. PMID: 24719335, PMCID: PMC4031537, DOI: 10.1074/jbc.m114.562264.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAsparagineBinding SitesBlotting, WesternCell LineCells, CulturedGlucosidasesGlycosylationHEK293 CellsHeLa CellsHumansIntracellular Signaling Peptides and ProteinsLysosomesMass SpectrometryMiceMice, KnockoutMicroscopy, FluorescenceMutationPolycystic Kidney, Autosomal DominantProtein Serine-Threonine KinasesProteolysisPyruvate Dehydrogenase Acetyl-Transferring KinaseConceptsGlucosidase IINon-catalytic β-subunitsProtein expressionFirst extracellular loopAutosomal dominant polycystic liver diseaseEfficient biogenesisGenetic interactionsMembrane proteinsBiochemical approachesN-glycosylationGenetic approachesTRPP2Glycosylation sitesBiological roleLysosomal degradationΒ-subunitChemical inhibitionBiogenesisExtracellular loopNonselective cation channelsIon channelsBiological importanceGlycosylationCation channelsProtein levels
2013
Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease
Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nature Genetics 2013, 45: 1004-1012. PMID: 23892607, PMCID: PMC3758452, DOI: 10.1038/ng.2715.Peer-Reviewed Original ResearchmiR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease
Patel V, Williams D, Hajarnis S, Hunter R, Pontoglio M, Somlo S, Igarashi P. miR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 10765-10770. PMID: 23759744, PMCID: PMC3696812, DOI: 10.1073/pnas.1301693110.Peer-Reviewed Original ResearchConceptsMiRNA clusterKidney cyst growthPolycystic kidney diseasePosttranscriptional gene expressionCyst growthOncogenic miRNA clusterShort noncoding RNAsKidney-specific inactivationKidney cyst formationDysregulated miRNA expressionPosttranscriptional repressionNoncoding RNAsHyperproliferative epithelial cellsGene dosageGene expressionHepatocyte nuclear factor-1βGenes PKD1Common genetic causeMiRNA expressionMouse modelFluid-filled cystsMiRNAsKidney diseaseTransgenic overexpressionKidney cysts
2012
Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels
Peyronnet R, Sharif-Naeini R, Folgering JH, Arhatte M, Jodar M, Boustany C, Gallian C, Tauc M, Duranton C, Rubera I, Lesage F, Pei Y, Peters DJ, Somlo S, Sachs F, Patel A, Honoré E, Duprat F. Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels. Cell Reports 2012, 1: 241-250. PMID: 22832196, PMCID: PMC3437542, DOI: 10.1016/j.celrep.2012.01.006.Peer-Reviewed Original ResearchMeSH KeywordsAcidosisActin CytoskeletonAnimalsApoptosisChlorocebus aethiopsCOS CellsCytoprotectionDocosahexaenoic AcidsGene Knockout TechniquesIon Channel GatingKidney Tubules, ProximalMechanotransduction, CellularMiceMice, KnockoutMutant ProteinsPotassium Channels, Tandem Pore DomainProtein SubunitsStress, MechanicalTRPP Cation ChannelsConceptsEpithelial cellsRenal epithelial cellsProximal convoluted tubule epithelial cellsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseKidney disease statesTubule epithelial cellsPolycystic kidney diseaseHeart failureKidney diseaseImportant pathologiesDisease statesApoptotic cell deathTREK-2K2P channelsCell deathApoptosisCellsAtherosclerosisDiseasePathologyEvaluation of urine biomarkers of kidney injury in polycystic kidney disease
Parikh CR, Dahl NK, Chapman AB, Bost JE, Edelstein CL, Comer DM, Zeltner R, Tian X, Grantham JJ, Somlo S. Evaluation of urine biomarkers of kidney injury in polycystic kidney disease. Kidney International 2012, 81: 784-790. PMID: 22258321, PMCID: PMC3319327, DOI: 10.1038/ki.2011.465.Peer-Reviewed Original ResearchMeSH KeywordsAcute-Phase ProteinsAdultAnimalsBiomarkersDisease ProgressionFemaleHumansInterleukin-18KidneyKidney Failure, ChronicLipocalin-2LipocalinsLongitudinal StudiesMaleMiceMice, KnockoutMice, TransgenicOncogene ProteinsPolycystic Kidney, Autosomal DominantProto-Oncogene ProteinsRatsRats, Mutant StrainsRats, Sprague-DawleyReceptors, Interleukin-18TRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseaseTotal kidney volumeKidney volumeIL-18Polycystic kidney diseaseKidney diseaseCyst fluidRenal tubular integrityIL-18 levelsRenal Disease equationSerial urine samplesGlomerular filtration rateModification of DietExpression of Lcn2Min/yearPolycystic Kidney Disease (CRISP) studyUrine of patientsDominant polycystic kidney diseaseKidney Disease studyUrinary collecting systemMean percentage increaseSPRD rat modelUrinary NGALUrine NGALKidney injury