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 targetsGenetic Analysis of Severe Polycystic Liver Disease in Japan.
Mizuno H, Besse W, Sekine A, Long K, Kurihara S, Oba Y, Yamanouchi M, Hasegawa E, Suwabe T, Sawa N, Ubara Y, Somlo S, Hoshino J. Genetic Analysis of Severe Polycystic Liver Disease in Japan. Kidney360 2024 PMID: 38689396, DOI: 10.34067/kid.0000000000000461.Peer-Reviewed Original ResearchSevere polycystic liver diseaseAutosomal dominant polycystic kidney diseaseDisease genesPolycystic liver diseasePKD2 patientsGenetic analysisWhole-exome sequencingSuspected pathogenic variantsLiver diseaseSpectrum of phenotypesPKD2 variantsExome sequencingAutosomal dominant polycystic kidney disease cohortPathogenic variantsPKD2PKD1Genetic etiologyDominant polycystic kidney diseaseGenesPolycystic kidney diseaseKidney cystsNo significant differenceKidney volumePLD patientsKidney diseaseA 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
2023
Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease
Schönauer R, Sierks D, Boerrigter M, Jawaid T, Caroff L, Audrezet M, Friedrich A, Shaw M, Degenhardt J, Forberger M, de Fallois J, Bläker H, Bergmann C, Gödiker J, Schindler P, Schlevogt B, Müller R, Berg T, Patterson I, Griffiths W, Sayer J, Consortium G, Ambrose J, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred C, Brittain H, Caulfield M, Chan G, Elgar G, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard T, Jackson R, Jones L, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Leigh S, Leong I, Lopez J, Maleady-Crowe F, McEntagart M, Minneci F, Moutsianas L, Mueller M, Murugaesu N, Need A, O’Donovan P, Odhams C, Patch C, Pereira M, Perez-Gil D, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott R, Siddiq A, Sieghart A, Smith S, Sosinsky A, Stuckey A, Tanguy M, Tavares A, Thomas E, Thompson S, Tucci A, Welland M, Williams E, Witkowska K, Wood S, Popp B, Torres V, Hogan M, Somlo S, Watnick T, Nevens F, Besse W, Gall E, Harris P, Drenth J, Halbritter J. Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease. Gastroenterology 2023, 166: 902-914. PMID: 38101549, DOI: 10.1053/j.gastro.2023.12.007.Peer-Reviewed Original ResearchAutosomal dominant polycystic liver diseasePolycystic liver diseaseDisease-related hospitalizationsLiver diseaseLiver eventsPathogenic variantsPrimary clinical end pointCombination of female sexCohort of patientsClinical end pointsInternational multicenter cohortPrediction of disease progressionGenotype-phenotype correlationPrimary clinical endpointTotal liver volumeUnderlying genetic defectSymptomatic hepatomegalyDesign of randomized controlled trialsRandomized controlled trialsFemale patientsIndependent of sexMulticenter cohortFemale preponderanceRare conditionSymptomatic diseaseInactivation of Ire1alpha Endoribonuclease Domain Slows Down ADPKD in Orthologous Mouse Models
Bhardwaj R, Volpe I, Yilmaz D, Pioppini C, Roy K, Rehman M, Cai Y, Krappitz M, Somlo S, Fedeles S. Inactivation of Ire1alpha Endoribonuclease Domain Slows Down ADPKD in Orthologous Mouse Models. Journal Of The American Society Of Nephrology 2023, 34: 19-19. DOI: 10.1681/asn.20233411s119b.Peer-Reviewed Original ResearchDephosphorylation Facilitates Trafficking of Mutant Polycystin-2 to Cilia
Cai Y, Dong K, Spitzer M, Geiges L, Tian X, Krappitz M, Diggs L, Wei Z, Cordido A, Pei S, Fedeles S, Somlo S. Dephosphorylation Facilitates Trafficking of Mutant Polycystin-2 to Cilia. Journal Of The American Society Of Nephrology 2023, 34: 560-560. DOI: 10.1681/asn.20233411s1560b.Peer-Reviewed Original ResearchCorrigendum to “WCN23-1242 Genetic interaction between XBP1 and Pkd1 modulates ADPKD progression” [Kidney International Reports Volume 8, Issue 3, Supplement, March 2023, Page S250]
Krappitz M, Pioppini C, Bhardwaj R, Duygu E, Hollmann T, Somlo S, Fedeles S. Corrigendum to “WCN23-1242 Genetic interaction between XBP1 and Pkd1 modulates ADPKD progression” [Kidney International Reports Volume 8, Issue 3, Supplement, March 2023, Page S250]. Kidney International Reports 2023, 8: 2182. PMID: 37850015, PMCID: PMC10577355, DOI: 10.1016/j.ekir.2023.08.001.Peer-Reviewed Original ResearchThe 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 strategiesProteinPhenotypeFragmentsHypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease
Gulati A, Dahl N, Hartung E, Clark S, Moudgil A, Goodwin J, Somlo S. Hypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease. Kidney360 2023, 4: 387-392. PMID: 36706243, PMCID: PMC10103195, DOI: 10.34067/kid.0000000000000064.Peer-Reviewed Original Research
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 ResearchXBP1 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 expressionAn update on ductal plate malformations and fibropolycystic diseases of the liver
Mirza H, Besse W, Somlo S, Weinreb J, Kenney B, Jain D. An update on ductal plate malformations and fibropolycystic diseases of the liver. Human Pathology 2022, 132: 102-113. PMID: 35777701, DOI: 10.1016/j.humpath.2022.06.022.Peer-Reviewed Original ResearchConceptsDuctal plate malformationLiver diseaseAdult polycystic liver diseaseAutosomal dominant polycystic kidneyFibropolycystic liver diseaseIsolated liver involvementCongenital hepatic fibrosisPolycystic liver diseaseVon Meyenburg complexesGenetic underpinningsMultiple clinical phenotypesFibropolycystic diseasePortal hypertensionCaroli's diseaseLiver involvementLiver cystsMeyenburg complexesHepatic fibrosisFibrocystic lesionsHepatocellular malignanciesCyst enlargementAbnormal organ developmentPolycystic kidneysAnimal modelsHepatocellular malignancyGenetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Participants K, Köttgen A, Gall E, Halbritter J, Kiryluk K, Mallett A, Parekh R, Rasouly H, Sampson M, Tin A, Antignac C, Ars E, Bergmann C, Bleyer A, Bockenhauer D, Devuyst O, Florez J, Fowler K, Franceschini N, Fukagawa M, Gale D, Gbadegesin R, Goldstein D, Grams M, Greka A, Gross O, Guay-Woodford L, Harris P, Hoefele J, Hung A, Knoers N, Kopp J, Kretzler M, Lanktree M, Lipska-Ziętkiewicz B, Nicholls K, Nozu K, Ojo A, Parsa A, Pattaro C, Pei Y, Pollak M, Rhee E, Sanna-Cherchi S, Savige J, Sayer J, Scolari F, Sedor J, Sim X, Somlo S, Susztak K, Tayo B, Torra R, van Eerde A, Weinstock A, Winkler C, Wuttke M, Zhang H, King J, Cheung M, Jadoul M, Winkelmayer W, Gharavi A. Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney International 2022, 101: 1126-1141. PMID: 35460632, PMCID: PMC9922534, DOI: 10.1016/j.kint.2022.03.019.Peer-Reviewed Original ResearchConceptsUse of genomicsUse of geneticsGenetic findingsGenome variationNumerous genesMolecular dataGenetic dataComplex kidney diseaseGenetic variantsGeneticsGenesEnvironmental factorsPolygenic scoresMonogenic kidney diseaseGenomicsChronic kidney diseaseImproved diagnosticsInheritanceKidney diseaseData resourcesOpen data resourcesPhenotyping
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 cellsDeathRenal plasticity revealed through reversal of polycystic kidney disease in mice
Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, Somlo S. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nature Genetics 2021, 53: 1649-1663. PMID: 34635846, PMCID: PMC9278957, DOI: 10.1038/s41588-021-00946-4.Peer-Reviewed Original ResearchConceptsPKD genesAutosomal dominant polycystic kidney diseaseCyst cell proliferationGene functionPolycystic kidney diseaseCell shapeGenesKidney diseaseExtracellular matrix depositionCell proliferationKidney tubule cellsNormal lumensDominant polycystic kidney diseaseUnexpected capacityPhenotypic featuresCyst progressionMatrix depositionCellsPlasticityCyst formationCystic tubulesMyofibroblast activationProliferationSquamoid cellsKidney resultsA polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts
Grosch M, Brunner K, Ilyaskin AV, Schober M, Staudner T, Schmied D, Stumpp T, Schmidt KN, Madej MG, Pessoa TD, Othmen H, Kubitza M, Osten L, de Vries U, Mair MM, Somlo S, Moser M, Kunzelmann K, Ziegler C, Haerteis S, Korbmacher C, Witzgall R. A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts. Journal Of Cell Science 2021, 134: jcs259013. PMID: 34345895, PMCID: PMC8435292, DOI: 10.1242/jcs.259013.Peer-Reviewed Original ResearchFC 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 starvationRestoration of proximal tubule flow-activated transport prevents cyst growth in polycystic kidney disease
Du Z, Tian X, Ma M, Somlo S, Weinstein AM, Wang T. Restoration of proximal tubule flow-activated transport prevents cyst growth in polycystic kidney disease. JCI Insight 2021, 6: e146041. PMID: 33886508, PMCID: PMC8262298, DOI: 10.1172/jci.insight.146041.Peer-Reviewed Original ResearchConceptsGlomerular filtration rateGlomerulotubular balanceRenal cyst formationCyst formationReceptor 1 antagonistPolycystic kidney diseaseKidney weightUntreated miceDA1 antagonistControl miceKidney diseaseFiltration rateFractional reabsorptionCystic indexMouse modelCyst growthConditional KOHCO3- absorptionHeterozygous miceSame antagonistsMicePT transportAntagonistEpithelial ciliaHCO3- transport
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 mechanismsMutationsMiceAdult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease.
Besse W, Roosendaal C, Tuccillo L, Roy SG, Gallagher AR, Somlo S. Adult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease. Kidney360 2020, 1: 1068-1076. PMID: 33554127, PMCID: PMC7861569, DOI: 10.34067/kid.0002522020.Peer-Reviewed Original ResearchConceptsAutosomal recessive polycystic kidney diseaseSomatic second-hit mutationsAutosomal dominant polycystic kidney diseaseSecond-hit mutationsPolycystic liver diseaseLiver phenotypePolycystic kidney diseaseBile duct homeostasisSecond hit mutationLiver cystsLiver diseaseKidney diseaseCyst formationGenetic interactionsPattern of inheritanceDisease genesRecessive polycystic kidney diseaseGermline inheritanceDominant polycystic kidney diseaseDuctal plate formationWeeks of ageRecessive genotypeSubset of adultsSomatic mutationsPlate format