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 targets
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 mechanismsMutationsMiceLoss of Cilia Does Not Slow Liver Disease Progression in Mouse Models of Autosomal Recessive Polycystic Kidney Disease.
Gallagher AR, Somlo S. Loss of Cilia Does Not Slow Liver Disease Progression in Mouse Models of Autosomal Recessive Polycystic Kidney Disease. Kidney360 2020, 1: 962-968. PMID: 33829210, PMCID: PMC8023589, DOI: 10.34067/kid.0001022019.Peer-Reviewed Original Research
2018
Ganetespib 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
2017
Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease
Wang Q, Cobo-Stark P, Patel V, Somlo S, Han PL, Igarashi P. Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease. Kidney International 2017, 93: 403-415. PMID: 29042084, PMCID: PMC5794572, DOI: 10.1016/j.kint.2017.08.005.Peer-Reviewed Original ResearchConceptsPolycystic kidney diseaseOrthologous mouse modelSingle mutant miceMutant miceRenal epithelial cellsCyst growthCAMP levelsKidney diseaseEpithelial cellsMouse modelTreatment of PKDA-kinase anchoring protein 150Renal cyclic AMPKidneys of miceCyclic AMPDouble mutant miceRenal cAMP levelsInhibition of AC5Kidney injuryLevels of cAMPPrimary ciliaKidney enlargementKidney functionCyst indexMiceCiliary 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
mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex
Pema M, Drusian L, Chiaravalli M, Castelli M, Yao Q, Ricciardi S, Somlo S, Qian F, Biffo S, Boletta A. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nature Communications 2016, 7: 10786. PMID: 26931735, PMCID: PMC4778067, DOI: 10.1038/ncomms10786.Peer-Reviewed Original ResearchConceptsPolycystin-1Genetic interaction studiesTSC genesPolycystic kidney diseaseTuberous sclerosis complex (TSC) genesKidney-specific inactivationPolycystin-1 expressionRenal cyst formationComplex genesContiguous gene syndromeGenesTsc1 mutantsAutosomal dominant polycystic kidney diseaseOpen new perspectivesDominant polycystic kidney diseaseCyst expansionMTOR inhibitorsNew interplayInteraction studiesTuberous sclerosis complexPKD1 mutationsInactivationCyst formationBiogenesisImportant role
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 mediatorThe Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees
Antignac C, Calvet JP, Germino GG, Grantham JJ, Guay-Woodford LM, Harris PC, Hildebrandt F, Peters DJ, Somlo S, Torres VE, Walz G, Zhou J, Yu AS. The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees. Journal Of The American Society Of Nephrology 2015, 26: 2081-2095. PMID: 25952256, PMCID: PMC4552123, DOI: 10.1681/asn.2014121192.Peer-Reviewed Original ResearchAnimalsBiomedical ResearchCiliaGenes, ModifierHumansKidney TubulesMechanistic Target of Rapamycin Complex 1Microtubule-Associated ProteinsMolecular Targeted TherapyMultiprotein ComplexesPhenotypePolycystic Kidney, Autosomal DominantRenal InsufficiencySignal TransductionTOR Serine-Threonine KinasesTRPP Cation Channels
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
2013
Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease
Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nature Genetics 2013, 45: 1004-1012. PMID: 23892607, PMCID: PMC3758452, DOI: 10.1038/ng.2715.Peer-Reviewed Original Research