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 strategiesProteinPhenotypeFragments
2022
AMPK and Polycystic Kidney Disease Drug Development: An Interesting Off-Target Target
Caplan MJ. AMPK and Polycystic Kidney Disease Drug Development: An Interesting Off-Target Target. Frontiers In Medicine 2022, 9: 753418. PMID: 35174190, PMCID: PMC8841847, DOI: 10.3389/fmed.2022.753418.Peer-Reviewed Original ResearchCellular signaling pathwaysPolycystic kidney diseasePolycystic kidney disease mutationCellular energy useProtein kinaseMaster regulatorCellular metabolismSignaling pathwaysDisease mutationsGenetic diseasesTissue architectureEnzyme activityDramatic perturbationsAutosomal dominant polycystic kidney diseasePathwayDominant polycystic kidney diseaseNew therapeuticsMutationsRenal tissue architectureDrug developmentCellsKinaseAMPKGeneration pathwaysGenes
2021
β3 adrenergic receptor as potential therapeutic target in ADPKD
Schena G, Carmosino M, Chiurlia S, Onuchic L, Mastropasqua M, Maiorano E, Schena FP, Caplan MJ. β3 adrenergic receptor as potential therapeutic target in ADPKD. Physiological Reports 2021, 9: e15058. PMID: 34676684, PMCID: PMC8531837, DOI: 10.14814/phy2.15058.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseΒ3-ARΒ3-adrenergic receptorTherapeutic targetKidney/body weight ratioΒ3-AR levelSympathetic nerve activityBody weight ratioType 2 receptorCyst-lining epithelial cellsDominant polycystic kidney diseaseRenal tubular cellsNovel therapeutic targetCyclic AMP accumulationPotential therapeutic targetVasopressin type 2 receptorHuman renal tissuePolycystic kidney diseaseFluid-filled cystsADPKD mouse modelNerve activityKidney functionKidney diseaseRenal parenchymaHealthy controls
2020
A cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling
Padovano V, Mistry K, Merrick D, Gresko N, Caplan MJ. A cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling. Cellular Signalling 2020, 72: 109634. PMID: 32283256, PMCID: PMC7269866, DOI: 10.1016/j.cellsig.2020.109634.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin proteinsG proteinsPolycystin-1 proteinProtein maturationTerminal tailObligate stepBiological pathwaysProtein cleavagePhysiological functionsProteolytic siteProteinPathological consequencesAutosomal dominant polycystic kidney diseaseTraffickingDominant polycystic kidney diseasePolycystic kidney diseasePrimary functionCleavageRegulationMaturationGenesMitochondriaValuable insightsPathway
2018
Metabolism and mitochondria in polycystic kidney disease research and therapy
Padovano V, Podrini C, Boletta A, Caplan MJ. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nature Reviews Nephrology 2018, 14: 678-687. PMID: 30120380, DOI: 10.1038/s41581-018-0051-1.Peer-Reviewed Original ResearchConceptsPolycystic kidney disease 1Polycystin-1Autosomal dominant polycystic kidney diseaseHallmark of ADPKDFluid-filled renal cystsPolycystin proteinsADPKD cellsPKD genesMolecular mechanismsOxidative phosphorylationCell metabolismRegulatory rolePhysiological functionsADPKD pathogenesisEnergy metabolismPotential therapeutic targetMonogenic diseasesEnergy productionMitochondriaDominant polycystic kidney diseasePolycystic kidney diseaseTherapeutic targetMutationsAlternative pathwayMetabolism
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 disease
2013
Polycystin-1 cleavage and the regulation of transcriptional pathways
Merrick D, Bertuccio CA, Chapin HC, Lal M, Chauvet V, Caplan MJ. Polycystin-1 cleavage and the regulation of transcriptional pathways. Pediatric Nephrology 2013, 29: 505-511. PMID: 23824180, PMCID: PMC3844055, DOI: 10.1007/s00467-013-2548-y.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseFluid-filled renal cystsPolycystin-2Transcriptional pathwaysPolycystin-1Primary ciliaProtein productsPhysiological functionsCommon genetic causeParent proteinProteolytic cleavageCleavage fragmentsGenetic causeGenesEnd-stage renal diseaseDominant polycystic kidney diseasePolycystic kidney diseaseBiological activityPathwayRenal diseaseKidney diseaseCleavageRenal parenchymaFragmentsRenal cystsPolycystin-1C terminus cleavage and its relation with polycystin-2, two proteins involved in polycystic kidney disease.
Bertuccio CA, Caplan MJ. Polycystin-1C terminus cleavage and its relation with polycystin-2, two proteins involved in polycystic kidney disease. Medicina 2013, 73: 155-62. PMID: 23570767.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin-2Autosomal dominant polycystic kidney diseaseTerminal cytoplasmic tailProtein sortingNormal tubulogenesisPolycystic kidney diseaseProtein functionCytoplasmic tailTerminal tailCommon genetic causeCystogenic processExtracellular matrixDifferentiation mechanismsCellular proliferationGenetic causeMultiple cleavagesDominant polycystic kidney diseasePathwayHigh proliferative rateCleavageProliferative rateSecretory characteristicsGenesTubulogenesisChapter 80 Autosomal Dominant Polycystic Kidney Disease
Somlo S, Torres V, Caplan M. Chapter 80 Autosomal Dominant Polycystic Kidney Disease. 2013, 2645-2688. DOI: 10.1016/b978-0-12-381462-3.00080-x.Peer-Reviewed Original ResearchAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseKidney diseasePolycystic kidney diseaseStructural kidney diseaseMultiple renal cystsAortic root dilatationTherapeutic clinical trialsMitral valve prolapseAbdominal wall herniasLiver bile ductsAge-dependent occurrenceBasic disease mechanismsNoncystic manifestationsRoot dilatationBile ductPolycystic liverSystemic disordersValve prolapseExtrarenal manifestationsClinical trialsPancreatic ductWall herniasRenal cystsClinical disease
2011
Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis
Takiar V, Nishio S, Seo-Mayer P, King JD, Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 2462-2467. PMID: 21262823, PMCID: PMC3038735, DOI: 10.1073/pnas.1011498108.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorRenal cystogenesisProtein kinaseAutosomal dominant polycystic kidney diseaseFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorEpithelial cellsCyst epithelial cellsRenal cyst developmentCyst-lining epithelial cellsAMPK activationConductance regulatorRapamycin (mTOR) pathwayMammalian targetPharmacological activatorsChloride channelsMTOR pathwayCystogenesisCyst developmentKinaseAMPKContext of ADPKDSignificant arrestDominant polycystic kidney diseasePolycystic kidney disease
2010
Polycystic kidney disease: Pathogenesis and potential therapies
Takiar V, Caplan MJ. Polycystic kidney disease: Pathogenesis and potential therapies. Biochimica Et Biophysica Acta 2010, 1812: 1337-1343. PMID: 21146605, PMCID: PMC3139769, DOI: 10.1016/j.bbadis.2010.11.014.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseRenal tubular epithelial cellsDominant polycystic kidney diseaseNovel therapeutic targetTubular epithelial cellsFluid-filled cystsRenal cyst formationRenal functionTreatment of PKDPathogenetic pathwaysPotential therapyTherapeutic targetDisease pathogenesisClinical therapyCyst formationInherited conditionEpithelial cellsDiseasePathogenesisTherapyPrimary ciliaCystsParenchymaThe cell biology of polycystic kidney disease
Chapin HC, Caplan MJ. The cell biology of polycystic kidney disease. Journal Of Cell Biology 2010, 191: 701-710. PMID: 21079243, PMCID: PMC2983067, DOI: 10.1083/jcb.201006173.Peer-Reviewed Original ResearchConceptsCell growth controlCell biological processesPolycystic kidney diseaseCell biologyBiological processesGrowth controlPKD2 geneFluid-filled cystsNovel therapeutic targetGenetic defectsAutosomal dominant polycystic kidney diseaseCommon genetic disorderNormal renal tubulesDominant polycystic kidney diseaseGenetic disordersTherapeutic targetDisease pathogenesisKidney diseaseMorphogenesisGenesNew lightPKD1BiologyMutationsRenal tubules
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
2005
The C-Terminal Tail of the Polycystin-1 Protein Interacts with the Na,K-ATPase α-Subunit
Zatti A, Chauvet V, Rajendran V, Kimura T, Pagel P, Caplan MJ. The C-Terminal Tail of the Polycystin-1 Protein Interacts with the Na,K-ATPase α-Subunit. Molecular Biology Of The Cell 2005, 16: 5087-5093. PMID: 16107561, PMCID: PMC1266409, DOI: 10.1091/mbc.e05-03-0200.Peer-Reviewed Original ResearchConceptsC-terminal tailPolycystin-1Cytoplasmic C-terminal tailK-ATPase α-subunitPolycystin-1 proteinK-ATPase activityRegulation of NaChinese hamster ovary cellsProtein interactsHamster ovary cellsProtein exhibitΑ-subunitFunctional studiesAmino acidsPKD1 geneOvary cellsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseasePolycystic kidney diseaseInteractsKinetic propertiesRegulationGenesTailProtein
2004
Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus
Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hieseberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. Journal Of Clinical Investigation 2004, 114: 1433-1443. PMID: 15545994, PMCID: PMC525739, DOI: 10.1172/jci21753.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell LineCell NucleusChlorocebus aethiopsCHO CellsCOS CellsCricetinaeCricetulusDogsEmbryo, MammalianEpithelial CellsKidney TubulesMembrane ProteinsMiceMice, TransgenicPolycystic Kidney, Autosomal DominantProteinsSequence DeletionSignal TransductionStress, MechanicalTranscription Factor AP-1TRPP Cation ChannelsConceptsC-terminal tailAutosomal dominant polycystic kidney diseaseCell-matrix interactionsCiliary signalingSecond genePolycystin-2Polycystin-1C-terminusNovel pathwayProteolytic cleavageNuclear translocationMechanical stimuliGenesDominant polycystic kidney diseasePolycystic kidney diseasePrecise mechanismCleavageTerminusSignalingTranslocationNucleusPathway
2003
Polycystin-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