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 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
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 Research
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 cellsDeath
2014
Altered trafficking and stability of polycystins underlie polycystic kidney disease
Cai Y, Fedeles SV, Dong K, Anyatonwu G, Onoe T, Mitobe M, Gao JD, Okuhara D, Tian X, Gallagher AR, Tang Z, Xie X, Lalioti MD, Lee AH, Ehrlich BE, Somlo S. Altered trafficking and stability of polycystins underlie polycystic kidney disease. Journal Of Clinical Investigation 2014, 124: 5129-5144. PMID: 25365220, PMCID: PMC4348948, DOI: 10.1172/jci67273.Peer-Reviewed Original ResearchConceptsG-protein-coupled receptor proteolytic sitePolycystic kidney diseaseKidney diseaseGPS cleavageAutosomal dominant polycystic kidney diseaseMissense mutationsDominant polycystic kidney diseasePolycystin-1Polycystin-2Murine modelSevere formPathogenic missense mutationsPKD1 mutationsCOOH-terminal fragmentDiseaseMissense variantsExpression levelsFunctional assaysCell-based systemsAltered trafficking
2010
Polycystin-2 Activation by Inositol 1,4,5-Trisphosphate-induced Ca2+ Release Requires Its Direct Association with the Inositol 1,4,5-Trisphosphate Receptor in a Signaling Microdomain*
Sammels E, Devogelaere B, Mekahli D, Bultynck G, Missiaen L, Parys JB, Cai Y, Somlo S, De Smedt H. Polycystin-2 Activation by Inositol 1,4,5-Trisphosphate-induced Ca2+ Release Requires Its Direct Association with the Inositol 1,4,5-Trisphosphate Receptor in a Signaling Microdomain*. Journal Of Biological Chemistry 2010, 285: 18794-18805. PMID: 20375013, PMCID: PMC2881802, DOI: 10.1074/jbc.m109.090662.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseGlutathione S-transferase pulldown experimentsEndoplasmic reticulumTrisphosphate receptorAgonist-induced intracellularTerminal ligand-binding domainMouse renal epithelial cellsTerminal cytoplasmic tailLigand-binding domainAdenoviral expression systemRenal epithelial cellsSignaling microdomainPathological mutantsPulldown experimentsTrisphosphate-induced Ca2Cytoplasmic tailAcidic clusterPolycystin-1Polycystin-2TRPP2Epithelial cellsExpression systemRegulation of ciliary trafficking of polycystin-2 and the pathogenesis of autosomal dominant polycystic kidney disease.
Cai Y, Tang Z. Regulation of ciliary trafficking of polycystin-2 and the pathogenesis of autosomal dominant polycystic kidney disease. Journal Of Central South University Medical Sciences 2010, 35: 93-9. PMID: 20197605, DOI: 10.3969/j.issn.1672-7347.2010.02.001.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseDominant polycystic kidney diseaseKidney diseasePathogenesis of ADPKDRenal epithelial cellsAccumulated evidenceEpithelial cellsKidney cystsDiseasePathogenesisPossible roleDisorder characteristicsPolycystin-1Polycystin-2Primary cilia
2009
Polycystin-1 C-terminal Cleavage Is Modulated by Polycystin-2 Expression*
Bertuccio CA, Chapin HC, Cai Y, Mistry K, Chauvet V, Somlo S, Caplan MJ. Polycystin-1 C-terminal Cleavage Is Modulated by Polycystin-2 Expression*. Journal Of Biological Chemistry 2009, 284: 21011-21026. PMID: 19491093, PMCID: PMC2742866, DOI: 10.1074/jbc.m109.017756.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAmino AcidsAnimalsCalciumCell NucleusChlorocebus aethiopsCOS CellsExtracellular SpaceGenes, ReporterHumansIntracellular SpaceMiceMutant ProteinsProteasome Endopeptidase ComplexProtein Processing, Post-TranslationalProtein TransportStructure-Activity RelationshipTRPP Cation Channels
2006
Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif
Geng L, Okuhara D, Yu Z, Tian X, Cai Y, Shibazaki S, Somlo S. Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. Journal Of Cell Science 2006, 119: 1383-1395. PMID: 16537653, DOI: 10.1242/jcs.02818.Peer-Reviewed Original Research
2004
Calcium Dependence of Polycystin-2 Channel Activity Is Modulated by Phosphorylation at Ser812 *
Cai Y, Anyatonwu G, Okuhara D, Lee KB, Yu Z, Onoe T, Mei CL, Qian Q, Geng L, Wiztgall R, Ehrlich BE, Somlo S. Calcium Dependence of Polycystin-2 Channel Activity Is Modulated by Phosphorylation at Ser812 *. Journal Of Biological Chemistry 2004, 279: 19987-19995. PMID: 14742446, DOI: 10.1074/jbc.m312031200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesBiotinylationCalciumCasein Kinase IICell MembraneDNA, ComplementaryEndoplasmic ReticulumGenes, DominantGlutathione TransferaseGlycosylationMembrane ProteinsMiceMice, Inbred BALB CMicroscopy, FluorescenceMutationPhosphatesPhosphorylationPrecipitin TestsProtein Serine-Threonine KinasesProtein Structure, TertiaryReverse Transcriptase Polymerase Chain ReactionSerineTime FactorsTRPP Cation ChannelsConceptsPolycystin-2Non-phosphorylated formChannel activityCation channelsCultured epithelial cellsActivation/inactivationPolycystic kidney diseaseProtein phosphorylationSubstitution mutantsNon-selective cation channelsConstitutive phosphorylationDivalent cation channelsPolycystin-1Substrate domainEndoplasmic reticulumPhosphorylationSingle-channel studiesVivo analysisControl cellsEpithelial cellsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseOpen probabilityCellsCK2
2003
Analysis of the Polycystins in Aortic Vascular Smooth Muscle Cells
Qian Q, Li M, Cai Y, Ward CJ, Somlo S, Harris PC, Torres VE. Analysis of the Polycystins in Aortic Vascular Smooth Muscle Cells. Journal Of The American Society Of Nephrology 2003, 14: 2280-2287. PMID: 12937304, DOI: 10.1097/01.asn.0000080185.38113.a3.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseVascular smooth muscle cellsSmooth muscle cellsAortic vascular smooth muscle cellsMuscle cellsSarcoplasmic reticulumCause of deathDominant polycystic kidney diseasePolycystic kidney diseasePolycystin-2Polycystin-1Kidney diseaseVascular phenotypeImmuno-gold electron microscopyADPKD proteinsTriton-X extractionPresent studyVivo interactionDense plaquesCell surface biotinylationCell surfacePlasma membranePolycystinsCellsSurface localizationPolycystin-1 Distribution Is Modulated by Polycystin-2 Expression in Mammalian Cells*
Grimm DH, Cai Y, Chauvet V, Rajendran V, Zeltner R, Geng L, Avner ED, Sweeney W, Somlo S, Caplan MJ. Polycystin-1 Distribution Is Modulated by Polycystin-2 Expression in Mammalian Cells*. Journal Of Biological Chemistry 2003, 278: 36786-36793. PMID: 12840011, DOI: 10.1074/jbc.m306536200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell LineCell MembraneCells, CulturedCOS CellsDNA, ComplementaryEndoplasmic ReticulumGene Expression RegulationMembrane ProteinsMiceMice, TransgenicMicroscopy, FluorescenceModels, BiologicalMutationPrecipitin TestsProtein BindingProtein BiosynthesisProteinsRecombinant Fusion ProteinsRNA, MessengerTransfectionTRPP Cation ChannelsConceptsPolycystin-1Polycystin-2Mammalian cellsLevel of expressionPolycystin-2 expressionEndoplasmic reticulumCell surfaceCOS-7 cellsNull cell lineRelative expression levelsSubcellular localizationFusion proteinGradient of expressionExpression levelsProteinCell linesPolycystinsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseDivergent patternsExpressionPolycystic kidney diseaseReticulumCellsLocalization
2002
Polycystin-2 is an intracellular calcium release channel
Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S. Polycystin-2 is an intracellular calcium release channel. Nature Cell Biology 2002, 4: 191-197. PMID: 11854751, DOI: 10.1038/ncb754.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcium ChannelsCalcium SignalingEndoplasmic ReticulumHumansIn Vitro TechniquesKidneyLLC-PK1 CellsMembrane PotentialsMembrane ProteinsMiceMice, Inbred C57BLMutationMutation, MissensePolycystic Kidney, Autosomal DominantRecombinant ProteinsSequence DeletionSignal TransductionSwineTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseaseIntracellular calcium release channelsPolycystic kidney diseaseCalcium release channelKidney diseaseTransient receptor potential channelsIntracellular calcium releaseDominant polycystic kidney diseaseRelease channelCalcium release signalsPolycystin-2 functionsType 2 autosomal dominant polycystic kidney diseaseCalcium releasePolycystin-2Single-channel studiesEpithelial cellsPotential channelsDiseaseMissense mutationsRelease signalsCarboxy-terminal truncationDisease-causing missense mutations
1998
Somatic Inactivation of Pkd2 Results in Polycystic Kidney Disease
Wu G, D'Agati V, Cai Y, Markowitz G, Park J, Reynolds D, Maeda Y, Le T, Hou H, Kucherlapati R, Edelmann W, Somlo S. Somatic Inactivation of Pkd2 Results in Polycystic Kidney Disease. Cell 1998, 93: 177-188. PMID: 9568711, DOI: 10.1016/s0092-8674(00)81570-6.Peer-Reviewed Original ResearchConceptsCellular recessive mechanismIntragenic homologous recombinationExon 1True null alleleMutant exon 1Somatic inactivationPkd2 resultsRenal cyst formationPKD2 proteinPolycystic kidney diseaseHomologous recombinationNull allelesHuman phenotypesPKD2 expressionUnstable alleleSomatic lossPKD2Autosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseMutationsGermline mutationsRecessive mechanismAllelesInactivationCyst formation
1997
Molecular Cloning, cDNA Sequence Analysis, and Chromosomal Localization of MousePkd2
Wu G, Mochizuki T, Le T, Cai Y, Hayashi T, Reynolds D, Somlo S. Molecular Cloning, cDNA Sequence Analysis, and Chromosomal Localization of MousePkd2. Genomics 1997, 45: 220-223. PMID: 9339380, DOI: 10.1006/geno.1997.4920.Peer-Reviewed Original ResearchConceptsCDNA sequenceIntegral membrane proteinsMembrane-spanning domainsCDNA sequence analysisAmino acid levelsGenomic localizationPKD2 mRNAChromosomal localizationMembrane proteinsMolecular cloningMouse mutationMurine homologueExpression analysisCandidate genesChromosome 5Sequence analysisMouse tissuesKidney phenotypePKD2CloningPolycystic kidney phenotypeGenesAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseasePolycystic kidney diseaseCharacterization of the Exon Structure of the Polycystic Kidney Disease 2 Gene (PKD2)
Hayashi T, Mochizuki T, Reynolds D, Wu G, Cai Y, Somlo S. Characterization of the Exon Structure of the Polycystic Kidney Disease 2 Gene (PKD2). Genomics 1997, 44: 131-136. PMID: 9286709, DOI: 10.1006/geno.1997.4851.Peer-Reviewed Original ResearchConceptsAG/GT rulePolycystic kidney disease 2 (PKD2) geneExon-intron structureIntegral membrane proteinsAutosomal dominant polycystic kidney diseaseTranslation start siteExon structurePositional cloningMembrane proteinsStart siteGenomic DNASplice acceptorPKD2 geneGenesExon 1Oligonucleotide primersHeteroduplex analysisPKD2Dominant polycystic kidney diseasePolycystic kidney diseaseMutation analysisCalcium channelsCloningSecond formExonsPKD1 interacts with PKD2 through a probable coiled-coil domain
Qian F, Germino F, Cai Y, Zhang X, Somlo S, Germino G. PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genetics 1997, 16: 179-183. PMID: 9171830, DOI: 10.1038/ng0697-179.Peer-Reviewed Original ResearchConceptsCoiled-coil domainC-terminusPKD1 gene productAutosomal dominant polycystic kidney diseaseSite-specific mutagenesisLarge cystic kidneysGene productsHomotypic interactionsTubular morphogenesisStructural basisHeterotypic interactionsPKD2TerminusRecent discoveryPathogenic mutationsDominant polycystic kidney diseasePKD1Cystic kidneysPolycystic kidney diseaseCommon pathwayAffected individualsMorphogenesisPolycystinsMutagenesisGenes
1996
PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein
Mochizuki T, Wu G, Hayashi T, Xenophontos S, Veldhuisen B, Saris J, Reynolds D, Cai Y, Gabow P, Pierides A, Kimberling W, Breuning M, Deltas C, Peters D, Somlo S. PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein. Science 1996, 272: 1339-1342. PMID: 8650545, DOI: 10.1126/science.272.5266.1339.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceCaenorhabditis elegansCalcium ChannelsChromosome MappingChromosomes, Human, Pair 4Cloning, MolecularConsensus SequenceCrystallography, X-RayFemaleGlycosylationHumansMaleMembrane ProteinsMolecular Sequence DataMutationPedigreePhenotypePolycystic Kidney, Autosomal DominantPolymorphism, Single-Stranded ConformationalProteinsSodium ChannelsTRPP Cation ChannelsConceptsCaenorhabditis elegans homologIntegral membrane proteinsAmino acid similarityPKD2 gene productCalcium-binding domainPKD2 proteinTransmembrane spansPolycystic kidney diseasePositional cloningPotential calcium-binding domainsSecond geneMembrane proteinsGene productsAcid sequenceIntracellular aminoNonsense mutationGenesAutosomal dominant polycystic kidney diseasePKD1Dominant polycystic kidney diseasePKD2 familiesProteinVoltage-activated calcium channelsHomologCalcium channels