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 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 cellsDeathFC 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 mechanismsMutationsMice
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 phenotype
2018
Polycystin-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
Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease
Ma M, Gallagher AR, Somlo S. Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease. Cold Spring Harbor Perspectives In Biology 2017, 9: a028209. PMID: 28320755, PMCID: PMC5666631, DOI: 10.1101/cshperspect.a028209.Peer-Reviewed Original ResearchConceptsPolycystin-2Autosomal dominant polycystic kidney diseaseCalcium-mediated signalsRole of ciliaDisruption of ciliaPolycystic kidney diseaseCellular processesCausal genesTransmembrane proteinTissue homeostasisCilia functionPrimary ciliaPolycystinsGenetic studiesHomeostatic maintenanceSignal integrationUnknown mechanismApical surfaceNephron structuresCiliaKidney tubule cellsIntact ciliaPrivileged compartmentActive remodelingTubule structure
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 phosphorylation
2015
Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation
Franco I, Margaria JP, De Santis MC, Ranghino A, Monteyne D, Chiaravalli M, Pema M, Campa CC, Ratto E, Gulluni F, Perez-Morga D, Somlo S, Merlo GR, Boletta A, Hirsch E. Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation. Journal Of The American Society Of Nephrology 2015, 27: 1135-1144. PMID: 26271513, PMCID: PMC4814170, DOI: 10.1681/asn.2014100967.Peer-Reviewed Original ResearchConceptsPI3K-C2αCiliary componentsPolycystin-2Primary ciliaRecycling endosome compartmentKidney cyst formationDuct 3 cellsCiliary entryCilium baseElongation defectsCargo proteinsCilium morphogenesisSubcellular locationPhosphoinositide 3Endosome compartmentTubule developmentProliferation signalsCiliary transportCyst formationCystic kidney diseaseIschemia/reperfusion-induced renal damageGenetic modelsCiliaCyst developmentKey mediator
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 traffickingPolycystin-1: a master regulator of intersecting cystic pathways
Fedeles SV, Gallagher AR, Somlo S. Polycystin-1: a master regulator of intersecting cystic pathways. Trends In Molecular Medicine 2014, 20: 251-260. PMID: 24491980, PMCID: PMC4008641, DOI: 10.1016/j.molmed.2014.01.004.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseAutosomal recessive polycystic kidney diseaseAutosomal dominant polycystic liver diseasePolycystic kidney diseaseKidney diseasePolycystic liver diseaseRecessive polycystic kidney diseaseDominant polycystic kidney diseaseLiver diseasePolycystic diseaseCyst growthLethal monogenic disorderCyst formationTranslational implicationsDiseaseMonogenic disordersCausative genesCystic phenotypeRecent dataPolycystin-1Polycystin-2Master regulator