2024
A 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 ResearchConceptsCyst 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
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
Glutamine 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 glutamine
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 mechanisms
2014
Steviol retards renal cyst growth through reduction of CFTR expression and inhibition of epithelial cell proliferation in a mouse model of polycystic kidney disease
Yuajit C, Muanprasat C, Gallagher AR, Fedeles SV, Kittayaruksakul S, Homvisasevongsa S, Somlo S, Chatsudthipong V. Steviol retards renal cyst growth through reduction of CFTR expression and inhibition of epithelial cell proliferation in a mouse model of polycystic kidney disease. Biochemical Pharmacology 2014, 88: 412-421. PMID: 24518257, DOI: 10.1016/j.bcp.2014.01.038.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseRenal cyst growthCyst-lining epithelial cellsMouse modelKidney diseaseEpithelial cell proliferationEffect of steviolCyst enlargementCyst growthCell proliferationEpithelial cellsBlood urea nitrogenHuman autosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseOrthologous mouse modelChloride channel expressionRenal epithelial cell proliferationTransepithelial fluid secretionADPKD mouse modelRenal failureKidney functionKidney weightDaily treatmentCreatinine values
2013
miR-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
Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation
Aguiari G, Bizzarri F, Bonon A, Mangolini A, Magri E, Pedriali M, Querzoli P, Somlo S, Harris PC, Catizone L, del Senno L. Polycystin-1 regulates amphiregulin expression through CREB and AP1 signalling: implications in ADPKD cell proliferation. Journal Of Molecular Medicine 2012, 90: 1267-1282. PMID: 22570239, PMCID: PMC4028691, DOI: 10.1007/s00109-012-0902-3.Peer-Reviewed Original ResearchMeSH KeywordsAmphiregulinAnimalsCell ProliferationCyclic AMPCyclic AMP Response Element-Binding ProteinEGF Family of ProteinsGene SilencingGlycoproteinsHEK293 CellsHumansIntercellular Signaling Peptides and ProteinsMiceMutagenesisMutationOligonucleotide Array Sequence AnalysisPhosphorylationPolycystic Kidney, Autosomal DominantPromoter Regions, GeneticSignal TransductionTranscription Factor AP-1TRPP Cation ChannelsConceptsActivator protein-1Cystic cellsCell proliferationFull-length PC1ADPKD cell proliferationCell growthEpidermal growth factor-like peptidesGrowth factor-like peptidesAutosomal dominant polycystic kidney diseaseRenal cyst developmentAbnormal cell proliferationChromatin immunoprecipitationPolycystin-1Key activatorEGFR activityMicroarray analysisAmphiregulin genesNew potential therapeutic targetsLuciferase assayFactor-like peptidesProtein 1Potential therapeutic targetCell linesAmphiregulin expressionCyst development