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 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 cellsDeath
2019
Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2
Kuo IY, Brill AL, Lemos FO, Jiang JY, Falcone JL, Kimmerling EP, Cai Y, Dong K, Kaplan DL, Wallace DP, Hofer AM, Ehrlich BE. Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2. Science Signaling 2019, 12 PMID: 31064883, PMCID: PMC6855602, DOI: 10.1126/scisignal.aat7397.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumPC2 knockdownMitochondrial CaCell culture modelKnockdown of Mfn2Polycystin-2 functionsHuman ADPKD kidneysAutosomal dominant polycystic kidney diseaseKey mitochondrial proteinsAberrant cell proliferationMitochondria-ER contactsCell proliferationER-mitochondrial interfaceKidney cystsIntimate functional relationshipNumerous fluid-filled cystsMitochondrial proteinsCyst-lining epithelial cellsMitofusin 2 expressionCulture modelPolycystin-2Knockdown cellsMitochondrial biogenesisMitofusin 2Mitochondrial respiration
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 ChannelsConceptsAutosomal dominant polycystic kidney diseaseCytoplasmic C-terminal tailDominant polycystic kidney diseaseLuciferase activityPolycystin-2 expressionPolycystic kidney diseasePolycystin-1Polycystin-2Kidney diseaseIntracellular Ca2
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 ResearchConceptsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseasePolycystic kidney diseasePolycystin-1Polycystin-2Kidney diseasePC2 expressionAmino acidsPrimary ciliaCiliaN-terminal 15 amino acidsCellsCOOH-terminalPathogenesisCystsDisease
2005
Polycystin-2 Regulates Proliferation and Branching Morphogenesis in Kidney Epithelial Cells*
Grimm DH, Karihaloo A, Cai Y, Somlo S, Cantley LG, Caplan MJ. Polycystin-2 Regulates Proliferation and Branching Morphogenesis in Kidney Epithelial Cells*. Journal Of Biological Chemistry 2005, 281: 137-144. PMID: 16278216, DOI: 10.1074/jbc.m507845200.Peer-Reviewed Original ResearchConceptsPolycystin-2Kidney epithelial cellsPolycystin-1Cell proliferationRegulation of tubulogenesisWild-type proteinMultiple fluid-filled cystsAutosomal dominant polycystic kidney diseaseTubule formationEpithelial cellsExtracellular-related kinaseRegulatory machineryPolycystin proteinsBranching morphogenesisNegative regulatorRespective proteinsGenes PKD1Regulates ProliferationChannel mutantsMorphogenesisFluid-filled cystsCell growthProper growthChannel activityProtein
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
Altered expression pattern of polycystin-2 in acute and chronic renal tubular diseases.
Obermüller N, Cai Y, Kränzlin B, Thomson RB, Gretz N, Kriz W, Somlo S, Witzgall R. Altered expression pattern of polycystin-2 in acute and chronic renal tubular diseases. Journal Of The American Society Of Nephrology 2002, 13: 1855-64. PMID: 12089381, DOI: 10.1097/01.asn.0000018402.33620.c7.Peer-Reviewed Original ResearchConceptsPolycystic kidney diseaseAutosomal dominant polycystic kidney diseaseKidney diseaseRenal failureDistal tubulesProximal tubulesIschemic acute renal failureCyst formationAcute renal failureAutosomal recessive polycystic kidney diseaseChronic renal failureRenal tubular diseaseCyst-lining cellsBasal compartmentPolycystin-2Renal injuryAcute injuryTubular diseaseKidney tissueAltered expression patternsPronounced upregulationNative kidney tissueS3 segmentDiseaseInjuryPolycystin-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
1999
The rat Pkd2 protein assumes distinct subcellular distributions in different organs
Obermüller N, Gallagher A, Cai Y, Gassler N, Gretz N, Somlo S, Witzgall R. The rat Pkd2 protein assumes distinct subcellular distributions in different organs. American Journal Of Physiology 1999, 277: f914-f925. PMID: 10600939, DOI: 10.1152/ajprenal.1999.277.6.f914.Peer-Reviewed Original ResearchConceptsPKD2 proteinDifferent cellular compartmentsDistinct subcellular distributionCellular compartmentsBasolateral distributionExpression patternsCytoplasmic locationSubcellular distributionPKD2 geneWidespread expressionCellular distributionAdrenal glandProteinSmooth muscle cellsSalivary glandsMuscle cellsPKD2Autosomal dominant polycystic kidney diseasePolycystic kidney diseaseDifferent organsRenal distal tubulesMutationsIndividual organsDifferent rat organsPKD2 mutationsAberrant splicing in the PKD2 gene as a cause of polycystic kidney disease.
Reynolds DM, Hayashi T, Cai Y, Veldhuisen B, Watnick TJ, Lens XM, Mochizuki T, Qian F, Maeda Y, Li L, Fossdal R, Coto E, Wu G, Breuning MH, Germino GG, Peters DJ, Somlo S. Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. Journal Of The American Society Of Nephrology 1999, 10: 2342-51. PMID: 10541293, DOI: 10.1681/asn.v10112342.Peer-Reviewed Original ResearchConceptsPolycystin-2Mutant polycystin-2Future functional studiesNovel intragenic polymorphismsFrame splice variantsMissense variantsSingle base substitution mutationsPolycystin-2 proteinCryptic splice siteAutosomal dominant polycystic kidney diseaseBase substitution mutationsTransmembrane spansSingle base substitutionPolycystic kidney diseaseSplicing signalsSubunit functionAberrant splicingLymphoblast RNAMutant chromosomesSplice siteSubstitution mutationsPKD2 geneThird mutationBase substitutionsSplice variantsIdentification and Characterization of Polycystin-2, thePKD2 Gene Product*
Cai Y, Maeda Y, Cedzich A, Torres V, Wu G, Hayashi T, Mochizuki T, Park J, Witzgall R, Somlo S. Identification and Characterization of Polycystin-2, thePKD2 Gene Product*. Journal Of Biological Chemistry 1999, 274: 28557-28565. PMID: 10497221, DOI: 10.1074/jbc.274.40.28557.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulum localizationPolycystin-2Gene productsPutative phosphorylation sitesProtein binding partnersProtein disulfide isomerasePKD2 gene productImmunofluorescent cell stainingIntegral membrane glycoproteinSubcellular fractionation studiesAutosomal dominant polycystic kidney diseaseEndo H resistanceGolgi proteinsPhosphorylation sitesSecond geneBinding partnerTruncation mutantsTranslation productsPlasma membraneHigh-mannose oligosaccharidesAcid regionEndoplasmic reticulumIntact cellsH resistanceMembrane glycoproteins