2024
Role of Valosin-Containing Protein (VCP) in Ciliary Morphology and ADPKD: Exploring VCP as a Novel Genetic Interactor in Disease Progression
Pioppini C, Bhardwaj R, Fedeles S, Yilmaz D, Krappitz M. Role of Valosin-Containing Protein (VCP) in Ciliary Morphology and ADPKD: Exploring VCP as a Novel Genetic Interactor in Disease Progression. Journal Of The American Society Of Nephrology 2024, 35: 10.1681/asn.2024w6rq11tc. DOI: 10.1681/asn.2024w6rq11tc.Peer-Reviewed Original ResearchQualitative Analysis and Comparison of Externally Led, Patient-Focused Drug Development (EL-PFDD) Concepts for Autosomal Recessive Polycystic Kidney Disease (ARPKD) against Standardized Outcomes in Nephrology (SONG) Initiatives
Soyfer B, Fedeles S, Vanasco W, Perrone R, Liebau M, Hartung E, Dell K, Guay-Woodford L, Hoover E, Oberdhan D. Qualitative Analysis and Comparison of Externally Led, Patient-Focused Drug Development (EL-PFDD) Concepts for Autosomal Recessive Polycystic Kidney Disease (ARPKD) against Standardized Outcomes in Nephrology (SONG) Initiatives. Journal Of The American Society Of Nephrology 2024, 35: 10.1681/asn.2024fj4z3w71. DOI: 10.1681/asn.2024fj4z3w71.Peer-Reviewed Original ResearchChemical Modulation of the Ire1α-Xbp1 Pathway Reduces Cyst Size in ADPKD Mouse and Human Three-Dimensional Spheroids
Hasan F, Bhardwaj R, Rehman M, Cai Y, Dong K, Cordido A, Pioppini C, Yilmaz D, Tian X, Somlo S, Krappitz M, Fedeles S. Chemical Modulation of the Ire1α-Xbp1 Pathway Reduces Cyst Size in ADPKD Mouse and Human Three-Dimensional Spheroids. Journal Of The American Society Of Nephrology 2024, 35: 10.1681/asn.2024x8qpvhm3. DOI: 10.1681/asn.2024x8qpvhm3.Peer-Reviewed Original ResearchA 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
Development of a Clinical Trial Enrichment (CTE) Tool for Autosomal Dominant Polycystic Kidney Disease
Aggarwal V, Zaph S, Leiser R, Quinlan L, Cui Z, Morales J, Miller C, Dasmahapatra P, Vanasco W, Romero K, Perrone R, Fedeles S. Development of a Clinical Trial Enrichment (CTE) Tool for Autosomal Dominant Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2023, 34: 206-206. DOI: 10.1681/asn.20233411s1206d.Peer-Reviewed Original ResearchInactivation 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 Research
2022
Polycystic Kidney Disease Drug Development: A Conference Report
Liebau M, Mekahli D, Perrone R, Soyfer B, Fedeles S. Polycystic Kidney Disease Drug Development: A Conference Report. Kidney Medicine 2022, 5: 100596. PMID: 36698747, PMCID: PMC9867973, DOI: 10.1016/j.xkme.2022.100596.Peer-Reviewed Original ResearchAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseAutosomal recessive polycystic kidney diseaseRecessive polycystic kidney diseaseKidney diseaseProgression of ADPKDSide effect profileChronic kidney failureDisease-modifying therapiesAutosomal dominant polycystic liver diseasePolycystic liver diseaseTotal kidney volumeDominant polycystic kidney diseaseCritical Path InstituteMechanism of actionCommon monogenic disorderDrug development toolsEffect profileLiver diseaseKidney failureOutcomes ConsortiumEnrichment biomarkerClinical trialsKidney volumeSurrogate endpointsXBP1 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 expressionDrug Development for Cystic Kidney Diseases
Fedeles S, Perrone RD. Drug Development for Cystic Kidney Diseases. Clinical Journal Of The American Society Of Nephrology 2022, 17: 1549-1550. PMID: 35998972, PMCID: PMC9528273, DOI: 10.2215/cjn.04910422.Peer-Reviewed Original Research
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
Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts
Ishikawa Y, Fedeles S, Marlier A, Zhang C, Gallagher AR, Lee AH, Somlo S. Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts. Journal Of The American Society Of Nephrology 2019, 30: 443-459. PMID: 30745418, PMCID: PMC6405156, DOI: 10.1681/asn.2018060614.Peer-Reviewed Original ResearchKidney injuryInterstitial inflammationKidney functional declineChronic kidney injuryRenal interstitial inflammationAutosomal dominant polycystic liver diseasePolycystic liver diseaseDistal nephron segmentsDouble knockout micePolycystic kidney diseaseEndoplasmic reticulum stressOvert activationRenal effectsKidney functionLiver diseaseKidney diseaseNeonatal miceFunctional declineNovel genetic modelMyofibroblast activationKnockout miceDisparate etiologiesLate onsetCollecting ductsNephron segments
2017
Isolated polycystic liver disease genes define effectors of polycystin-1 function
Besse W, Dong K, Choi J, Punia S, Fedeles SV, Choi M, Gallagher AR, Huang EB, Gulati A, Knight J, Mane S, Tahvanainen E, Tahvanainen P, Sanna-Cherchi S, Lifton RP, Watnick T, Pei YP, Torres VE, Somlo S. Isolated polycystic liver disease genes define effectors of polycystin-1 function. Journal Of Clinical Investigation 2017, 127: 3558-3558. PMID: 28862642, PMCID: PMC5669574, DOI: 10.1172/jci96729.Peer-Reviewed Original ResearchPolycystin-1 functionPolycystin-1Protein biogenesis pathwaysGenome-wide basisPolycystic liver diseaseLoss-of-function mutationsWhole-exome sequencingHeterozygous loss-of-function mutationsBiogenesis pathwayLoss of functionAdditional genesDisease genesGene productsCell line modelsCandidate genesExome sequencingEndoplasmic reticulumCausative genesFunction mutationsGenesAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseSec63Defective maturationKidney cystsIsolated polycystic liver disease genes define effectors of polycystin-1 function
Besse W, Dong K, Choi J, Punia S, Fedeles SV, Choi M, Gallagher AR, Huang EB, Gulati A, Knight J, Mane S, Tahvanainen E, Tahvanainen P, Sanna-Cherchi S, Lifton RP, Watnick T, Pei YP, Torres VE, Somlo S. Isolated polycystic liver disease genes define effectors of polycystin-1 function. Journal Of Clinical Investigation 2017, 127: 1772-1785. PMID: 28375157, PMCID: PMC5409105, DOI: 10.1172/jci90129.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsCalcium-Binding ProteinsCell Line, TransformedCystsEndoplasmic ReticulumFemaleGenome-Wide Association StudyGlucosidasesGlucosyltransferasesHeterozygoteHumansIntracellular Signaling Peptides and ProteinsLiver DiseasesMaleMembrane ProteinsMiceMolecular ChaperonesMutationRNA-Binding ProteinsSEC Translocation ChannelsTRPP Cation ChannelsConceptsPolycystin-1 functionPolycystin-1Protein biogenesis pathwaysGenome-wide basisPolycystic liver diseaseLoss-of-function mutationsWhole-exome sequencingHeterozygous loss-of-function mutationsBiogenesis pathwayLoss of functionAdditional genesDisease genesGene productsCell line modelsCandidate genesExome sequencingEndoplasmic reticulumCausative genesFunction mutationsGenesAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseSec63Defective maturationKidney cysts
2016
Is it Time to Fold the Cysts Away?
Krappitz M, Gallagher AR, Fedeles S. Is it Time to Fold the Cysts Away? Trends In Molecular Medicine 2016, 22: 997-999. PMID: 27793600, DOI: 10.1016/j.molmed.2016.10.001.Peer-Reviewed Original Research
2015
Hepatocystin is Essential for TRPM7 Function During Early Embryogenesis
Overton JD, Komiya Y, Mezzacappa C, Nama K, Cai N, Lou L, Fedeles SV, Habas R, Runnels LW. Hepatocystin is Essential for TRPM7 Function During Early Embryogenesis. Scientific Reports 2015, 5: 18395. PMID: 26671672, PMCID: PMC4680877, DOI: 10.1038/srep18395.Peer-Reviewed Original ResearchConceptsXenopus laevis embryosEmbryonic lethalityTRPM7 functionLaevis embryosProtein kinase C substrate 80KEarly embryonic lethalityNoncatalytic beta subunitXenopus laevis embryogenesisEmbryonic day E11.5TRPM7 ion channelVertebrate gastrulationGastrulation defectsResident enzymesEarly embryogenesisPolycystin-2TRPM7 protein expressionDay E11.5KDa proteinGlucosidase IIEndoplasmic reticulumBeta subunitOverexpression of TRPM7Second alleleSomatic lossIon channelsEssential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes
Hassan H, Tian X, Inoue K, Chai N, Liu C, Soda K, Moeckel G, Tufro A, Lee AH, Somlo S, Fedeles S, Ishibe S. Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes. Journal Of The American Society Of Nephrology 2015, 27: 1055-1065. PMID: 26303067, PMCID: PMC4814187, DOI: 10.1681/asn.2015020191.Peer-Reviewed Original ResearchConceptsX-box binding protein 1Endoplasmic reticulum stress responseEndoplasmic reticulum stressGlomerular filtration barrierPodocyte injuryReticulum stress responseBinding protein 1Reticulum stressProtein 1Filtration barrierFoot process effacementProgressive albuminuriaMouse modelProcess effacementUnfolded protein response pathwayEpithelial cellsNormal glomerular filtration barrierProtein response pathwayEndoplasmic reticulumPodocytesGenetic inactivationXBP1 pathwayInjuryJNK pathwayStress responseSec63 and Xbp1 regulate IRE1α activity and polycystic disease severity
Fedeles SV, So JS, Shrikhande A, Lee SH, Gallagher AR, Barkauskas CE, Somlo S, Lee AH. Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity. Journal Of Clinical Investigation 2015, 125: 1955-1967. PMID: 25844898, PMCID: PMC4463201, DOI: 10.1172/jci78863.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineDisease Models, AnimalDNA HelicasesDNA-Binding ProteinsEndoribonucleasesFemaleGlucosidasesIntracellular Signaling Peptides and ProteinsKidneyMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMolecular ChaperonesPolycystic Kidney, Autosomal DominantPolycystic Kidney, Autosomal RecessiveProtein Serine-Threonine KinasesProtein Structure, TertiaryReceptors, G-Protein-CoupledRecombinant Fusion ProteinsRegulatory Factor X Transcription FactorsRNA SplicingRNA, Small InterferingRNA-Binding ProteinsTranscription FactorsTransfectionTRPP Cation ChannelsUnfolded Protein ResponseX-Box Binding Protein 1ConceptsG protein-coupled receptor proteolysis siteCyst formationPolycystic liver diseaseGPS cleavagePolycystin-1IRE1α-XBP1 branchMurine genetic modelsPolycystic kidney phenotypeLiver diseasePolycystic diseaseCystic diseaseDisease manifestationsMurine modelDisease severityKidney phenotypeXBP1 activationUnfolded protein response pathwayDiseaseXBP1 overexpressionPC1 functionsProtein response pathwayEnforced expressionMiceXBP1Activation of XBP1
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