2024
Genetic Analysis of Severe Polycystic Liver Disease in Japan
Mizuno H, Besse W, Sekine A, Long K, Kurihara S, Oba Y, Yamanouchi M, Hasegawa E, Suwabe T, Sawa N, Ubara Y, Somlo S, Hoshino J. Genetic Analysis of Severe Polycystic Liver Disease in Japan. Kidney360 2024, 5: 1106-1115. PMID: 38689396, PMCID: PMC11371350, DOI: 10.34067/kid.0000000000000461.Peer-Reviewed Original ResearchSevere polycystic liver diseaseAutosomal dominant polycystic kidney diseaseDisease genesPolycystic liver diseasePKD2 patientsGenetic analysisWhole-exome sequencingSuspected pathogenic variantsLiver diseaseSpectrum of phenotypesPKD2 variantsExome sequencingAutosomal dominant polycystic kidney disease cohortPathogenic variantsPKD2PKD1Genetic etiologyDominant polycystic kidney diseaseGenesPolycystic kidney diseaseKidney cystsNo significant differenceKidney volumePLD patientsKidney diseaseGlis2 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 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
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 strategiesProteinPhenotypeFragmentsHypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease
Gulati A, Dahl N, Hartung E, Clark S, Moudgil A, Goodwin J, Somlo S. Hypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease. Kidney360 2023, 4: 387-392. PMID: 36706243, PMCID: PMC10103195, DOI: 10.34067/kid.0000000000000064.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseKidney diseaseDominant polycystic kidney diseasePolycystic kidney diseaseMild kidney disease
2022
Pkd2 Re-Expression Can Reverse Liver Cysts and Improve GFR in Mouse Models of Autosomal Dominant Polycystic Kidney Disease
Dong K, Tham M, Cordido A, Cai Y, Pei S, Bhardwaj R, Wei Z, Rehman M, Roy K, Tian X, Somlo S. Pkd2 Re-Expression Can Reverse Liver Cysts and Improve GFR in Mouse Models of Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2022, 33: 418-418. DOI: 10.1681/asn.20223311s1418c.Peer-Reviewed Original ResearchModel of autosomal dominant polycystic kidney diseaseMouse models of autosomal dominant polycystic kidney diseaseAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseasePolycystic kidney diseaseXBP1 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 ResearchConceptsProximal 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 resultsFC 008INTERDEPENDENT REGULATION OF POLYCYSTIN EXPRESSION INFLUENCES STARVATION-INDUCED AUTOPHAGY AND CELL DEATH
Decuypere J, Van Giel D, Janssens P, Dong K, Somlo S, Cai Y, Mekahli D, Vennekens R. FC 008INTERDEPENDENT REGULATION OF POLYCYSTIN EXPRESSION INFLUENCES STARVATION-INDUCED AUTOPHAGY AND CELL DEATH. Nephrology Dialysis Transplantation 2021, 36: gfab125.001. DOI: 10.1093/ndt/gfab125.001.Peer-Reviewed Original ResearchAutosomal dominant polycystic kidney diseaseEarly-stage ADPKD patientsProximal tubular epithelial cellsProteins polycystin-1Renal stressADPKD patientsEarly-stage autosomal dominant polycystic kidney diseasePC1 levelsCell deathCyst formationTruncating PKD1 mutationsSevere disease progressionAutophagy upregulationDominant polycystic kidney diseaseTubular epithelial cellsRenal cell survivalPolycystic kidney diseasePolycystin-2Cell survivalCell death resistanceKidney diseaseDisease progressionGFP-LC3 punctaeSiRNA-mediated knockdownChronic starvation
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 ResearchConceptsAutosomal 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 mechanismsMutationsMiceAdult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease.
Besse W, Roosendaal C, Tuccillo L, Roy SG, Gallagher AR, Somlo S. Adult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease. Kidney360 2020, 1: 1068-1076. PMID: 33554127, PMCID: PMC7861569, DOI: 10.34067/kid.0002522020.Peer-Reviewed Original ResearchConceptsAutosomal recessive polycystic kidney diseaseSomatic second-hit mutationsAutosomal dominant polycystic kidney diseaseSecond-hit mutationsPolycystic liver diseaseLiver phenotypePolycystic kidney diseaseBile duct homeostasisSecond hit mutationLiver cystsLiver diseaseKidney diseaseCyst formationGenetic interactionsPattern of inheritanceDisease genesRecessive polycystic kidney diseaseGermline inheritanceDominant polycystic kidney diseaseDuctal plate formationWeeks of ageRecessive genotypeSubset of adultsSomatic mutationsPlate formatCyclin-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
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 ResearchConceptsHedgehog 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 phenotypeALG9 Mutation Carriers Develop Kidney and Liver Cysts
Besse W, Chang AR, Luo JZ, Triffo WJ, Moore BS, Gulati A, Hartzel DN, Mane S, Center R, Torres VE, Somlo S, Mirshahi T. ALG9 Mutation Carriers Develop Kidney and Liver Cysts. Journal Of The American Society Of Nephrology 2019, 30: 2091-2102. PMID: 31395617, PMCID: PMC6830805, DOI: 10.1681/asn.2019030298.Peer-Reviewed Original ResearchConceptsProteins polycystin-1Autosomal dominant polycystic kidney diseaseDisease genesRare loss-of-function variantsN-glycan precursorsNovel disease genesLoss-of-function variantsEndoplasmic reticulum lumenLoss-of-function mutationsMonogenic kidney diseaseWhole-exome sequencingGenotype-phenotype correlationProtein biogenesisProtein maturationReticulum lumenPolycystin-1Endoplasmic reticulumGene productsPopulation-based cohortCell-based assaysPhenotypic characterizationPolycystic phenotypeMutation carrier stateDefective glycosylationDominant polycystic kidney disease
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 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