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 targetsA synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress
Fedeles B, Bhardwaj R, Ishikawa Y, Khumsubdee S, Krappitz M, Gubina N, Volpe I, Andrade D, Westergerling P, Staudner T, Campolo J, Liu S, Dong K, Cai Y, Rehman M, Gallagher A, Ruchirawat S, Croy R, Essigmann J, Fedeles S, Somlo S. A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2317344121. PMID: 38241440, PMCID: PMC10823221, DOI: 10.1073/pnas.2317344121.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell ProliferationCystsDNAKidneyMiceOxidative StressPolycystic Kidney DiseasesPolycystic Kidney, Autosomal DominantTRPP Cation ChannelsConceptsCyst cellsAutosomal dominant polycystic kidney diseaseMouse models of autosomal dominant polycystic kidney diseasePolycystic kidney diseaseModel of autosomal dominant polycystic kidney diseaseKidney diseaseDeveloped primersMitochondrial oxidative stressPathophysiology of autosomal dominant polycystic kidney diseaseOxidative stressInduce apoptosisMitochondrial respirationCystic cellsUp-regulating aerobic glycolysisHomozygous inactivationMonogenic causeDominant polycystic kidney diseaseAerobic glycolysisRenal replacement therapyApoptosisEnd-stage kidney diseaseAnti-tumor agentsAdult mouse modelChronic kidney diseaseAlkylate DNA
2023
The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X, Pandya R, Rai V, Gresko N, Ahmed O, Lam T, Wang W, Shen H, Somlo S, Caplan M. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nature Communications 2023, 14: 1790. PMID: 36997516, PMCID: PMC10063565, DOI: 10.1038/s41467-023-37449-1.Peer-Reviewed Original ResearchConceptsPolycystin-1Nicotinamide nucleotide transhydrogenaseTerminal tailCystic phenotypeAutosomal dominant polycystic kidney diseaseCyst cell proliferationC-terminal domainAmino acid residuesLethal monogenic disorderC-terminal cleavageNucleotide transhydrogenaseAcid residuesMitochondrial functionTransgenic expressionPKD1 geneRedox stateShort fragmentsCell proliferationMonogenic disordersDominant polycystic kidney diseasePolycystic kidney diseaseGene therapy strategiesProteinPhenotypeFragments
2022
XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice
Krappitz M, Bhardwaj R, Dong K, Staudner T, Yilmaz DE, Pioppini C, Westergerling P, Ruemmele D, Hollmann T, Nguyen TA, Cai Y, Gallagher AR, Somlo S, Fedeles S. XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice. Journal Of The American Society Of Nephrology 2022, 34: 110-121. PMID: 36270750, PMCID: PMC10101557, DOI: 10.1681/asn.2021091180.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin-2Functional polycystin-1Amino acid substitution mutationsAutosomal dominant polycystic kidney diseaseIntegral membrane proteinsTranscription factor XBP1Unfolded protein responsePost-translational maturationAcid substitution mutationsEndoplasmic reticulum chaperoneCiliary traffickingXBP1 activityChaperone functionIntegral membraneActive XBP1Polycystic kidney diseaseMembrane proteinsPC1 functionsPrimary ciliaProtein responseHypomorphic mutationsTransgenic activationSubstitution mutationsTransgenic expression
2021
Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death
Decuypere JP, Van Giel D, Janssens P, Dong K, Somlo S, Cai Y, Mekahli D, Vennekens R. Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death. International Journal Of Molecular Sciences 2021, 22: 13511. PMID: 34948309, PMCID: PMC8706473, DOI: 10.3390/ijms222413511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutophagyCell DeathCell LineEpithelial CellsHumansKidney Tubules, ProximalMicePolycystic Kidney, Autosomal DominantStarvationTRPP Cation ChannelsConceptsProximal tubular epithelial cellsAutosomal dominant polycystic kidney diseaseEarly-stage ADPKD patientsCell deathPC2 expressionDominant polycystic kidney diseaseTubular epithelial cellsRenal cell survivalPolycystin-1Polycystic kidney diseaseCell survivalPolycystin-2Basal autophagyAutophagic cell survivalCell death resistanceADPKD progressionKidney diseaseADPKD patientsLess cell deathPC1 levelsChronic starvationHealthy individualsDuct cellsEpithelial cellsDeathRenal plasticity revealed through reversal of polycystic kidney disease in mice
Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, Somlo S. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nature Genetics 2021, 53: 1649-1663. PMID: 34635846, PMCID: PMC9278957, DOI: 10.1038/s41588-021-00946-4.Peer-Reviewed Original ResearchConceptsPKD genesAutosomal dominant polycystic kidney diseaseCyst cell proliferationGene functionPolycystic kidney diseaseCell shapeGenesKidney diseaseExtracellular matrix depositionCell proliferationKidney tubule cellsNormal lumensDominant polycystic kidney diseaseUnexpected capacityPhenotypic featuresCyst progressionMatrix depositionCellsPlasticityCyst formationCystic tubulesMyofibroblast activationProliferationSquamoid cellsKidney resultsA polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts
Grosch M, Brunner K, Ilyaskin AV, Schober M, Staudner T, Schmied D, Stumpp T, Schmidt KN, Madej MG, Pessoa TD, Othmen H, Kubitza M, Osten L, de Vries U, Mair MM, Somlo S, Moser M, Kunzelmann K, Ziegler C, Haerteis S, Korbmacher C, Witzgall R. A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts. Journal Of Cell Science 2021, 134: jcs259013. PMID: 34345895, PMCID: PMC8435292, DOI: 10.1242/jcs.259013.Peer-Reviewed Original ResearchRestoration 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
Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease
Vien TN, Ng LCT, Smith JM, Dong K, Krappitz M, Gainullin VG, Fedeles S, Harris PC, Somlo S, DeCaen PG. Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease. Journal Of Cell Science 2020, 133: jcs255562. PMID: 33199522, PMCID: PMC7774883, DOI: 10.1242/jcs.255562.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCiliaEF Hand MotifsMicePolycystic Kidney DiseasesPolycystic Kidney, Autosomal DominantTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseDominant polycystic kidney diseaseChannel functionPhysiological membrane potentialsPolycystin-2Primary ciliaDuct cellsNew mouseChannel activityDiseaseIon channelsDistinct mutationsInternal CaMembrane potentialChannel regulationHand associationEF-hand Ca2Regulatory mechanismsMutationsMiceCyclin-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 knockoutProliferationLoss of Cilia Does Not Slow Liver Disease Progression in Mouse Models of Autosomal Recessive Polycystic Kidney Disease.
Gallagher AR, Somlo S. Loss of Cilia Does Not Slow Liver Disease Progression in Mouse Models of Autosomal Recessive Polycystic Kidney Disease. Kidney360 2020, 1: 962-968. PMID: 33829210, PMCID: PMC8023589, DOI: 10.34067/kid.0001022019.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCiliaDisease ProgressionLiverMicePolycystic Kidney, Autosomal RecessiveTRPP Cation Channels
2019
Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease
Ma M, Legué E, Tian X, Somlo S, Liem KF. Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2019, 30: 2103-2111. PMID: 31451534, PMCID: PMC6830786, DOI: 10.1681/asn.2018121274.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDisease Models, AnimalHedgehog ProteinsMicePolycystic Kidney, Autosomal DominantSignal TransductionTRPP Cation ChannelsZinc Finger Protein GLI1ConceptsHedgehog pathwayPolycystin-1Polycystin-2Autosomal dominant polycystic kidney diseaseMain causal genePolycystic kidney diseaseKidney cyst formationEpithelial cellsLevels of HedgehogCiliary genesDominant polycystic kidney diseaseMutant mouse kidneysRenal epithelial cellsCausal genesSignal transductionCell signalingGenetic manipulationPrimary ciliaCyst formationMultipass transmembraneHedgehog signalingConditional inactivationUnknown pathwayHedgehogKidney phenotype
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 expansionMonoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease
Gall E, Olson RJ, Besse W, Heyer CM, Gainullin VG, Smith JM, Audrézet MP, Hopp K, Porath B, Shi B, Baheti S, Senum SR, Arroyo J, Madsen CD, Férec C, Joly D, Jouret F, Fikri-Benbrahim O, Charasse C, Coulibaly JM, Yu AS, Khalili K, Pei Y, Somlo S, Le Meur Y, Torres VE, Group G, Group T, Disease T, Harris PC. Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. American Journal Of Human Genetics 2018, 102: 832-844. PMID: 29706351, PMCID: PMC5986722, DOI: 10.1016/j.ajhg.2018.03.013.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingEnd-stage renal diseaseAutosomal dominant polycystic kidney diseasePhenotypically similar familiesNext-generation sequencingDevelopment of kidney cystsCystic kidneysPolycystic kidney diseaseTargeted next-generation sequencingFrameshift changesInterstitial fibrosisKidney diseasePhenotypic hybridsMissense variantsMembrane proteinsTrafficking defectsADTKDEpisodes of goutLate-onset end-stage renal diseaseProgressive interstitial fibrosisAffected membersMultigenerational familiesCo-factorPhenotypic overlapPartial phenotypic overlapPolycystin-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 types
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 indexMiceIsolated polycystic liver disease genes define effectors of polycystin-1 function
Besse W, Dong K, Choi J, Punia S, Fedeles SV, Choi M, Gallagher AR, Huang EB, Gulati A, Knight J, Mane S, Tahvanainen E, Tahvanainen P, Sanna-Cherchi S, Lifton RP, Watnick T, Pei YP, Torres VE, Somlo S. Isolated polycystic liver disease genes define effectors of polycystin-1 function. Journal Of Clinical Investigation 2017, 127: 1772-1785. PMID: 28375157, PMCID: PMC5409105, DOI: 10.1172/jci90129.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsCalcium-Binding ProteinsCell Line, TransformedCystsEndoplasmic ReticulumFemaleGenome-Wide Association StudyGlucosidasesGlucosyltransferasesHeterozygoteHumansIntracellular Signaling Peptides and ProteinsLiver DiseasesMaleMembrane ProteinsMiceMolecular ChaperonesMutationRNA-Binding ProteinsSEC Translocation ChannelsTRPP Cation ChannelsConceptsPolycystin-1 functionPolycystin-1Protein biogenesis pathwaysGenome-wide basisPolycystic liver diseaseLoss-of-function mutationsWhole-exome sequencingHeterozygous loss-of-function mutationsBiogenesis pathwayLoss of functionAdditional genesDisease genesGene productsCell line modelsCandidate genesExome sequencingEndoplasmic reticulumCausative genesFunction mutationsGenesAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseSec63Defective maturationKidney cysts
2016
The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function
Padovano V, Kuo IY, Stavola LK, Aerni HR, Flaherty BJ, Chapin HC, Ma M, Somlo S, Boletta A, Ehrlich BE, Rinehart J, Caplan MJ. The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Molecular Biology Of The Cell 2016, 28: 261-269. PMID: 27881662, PMCID: PMC5231895, DOI: 10.1091/mbc.e16-08-0597.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin-2Cellular oxygen-sensing pathwaysMitochondrial functionOxygen-sensing pathwayBroad physiological rolesProlyl hydroxylase domainCellular energy metabolismPolycystin complexIon channel complexEndoplasmic reticulum CaPC1 expressionSubcellular localizationHydroxylase domainMitochondrial CaER CaNovel rolePhysiological roleEnergy metabolismChannel complexChannel activityPolycystinsAutosomal dominant polycystic kidney diseaseReticulum CaDominant polycystic kidney diseaseDouble 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 phosphorylationmTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex
Pema M, Drusian L, Chiaravalli M, Castelli M, Yao Q, Ricciardi S, Somlo S, Qian F, Biffo S, Boletta A. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nature Communications 2016, 7: 10786. PMID: 26931735, PMCID: PMC4778067, DOI: 10.1038/ncomms10786.Peer-Reviewed Original ResearchConceptsPolycystin-1Genetic interaction studiesTSC genesPolycystic kidney diseaseTuberous sclerosis complex (TSC) genesKidney-specific inactivationPolycystin-1 expressionRenal cyst formationComplex genesContiguous gene syndromeGenesTsc1 mutantsAutosomal dominant polycystic kidney diseaseOpen new perspectivesDominant polycystic kidney diseaseCyst expansionMTOR inhibitorsNew interplayInteraction studiesTuberous sclerosis complexPKD1 mutationsInactivationCyst formationBiogenesisImportant role