2017
Loss of the podocyte glucocorticoid receptor exacerbates proteinuria after injury
Zhou H, Tian X, Tufro A, Moeckel G, Ishibe S, Goodwin J. Loss of the podocyte glucocorticoid receptor exacerbates proteinuria after injury. Scientific Reports 2017, 7: 9833. PMID: 28852159, PMCID: PMC5575043, DOI: 10.1038/s41598-017-10490-z.Peer-Reviewed Original ResearchConceptsKnockout miceGlucocorticoid receptorNephrotic syndromeSimilar renal functionMainstay of therapyReceptor knockout miceTreatment of proteinuriaFoot process effacementMechanism of actionImmunomodulatory therapyRenal functionGlomerular injuryProtein excretionKO miceCommon disorderNephrotoxic serumPodocyte injuryPodocyte-specific deletionMouse modelSlit diaphragm proteinsWild-type podocytesProcess effacementProteinuriaUnstimulated conditionsKnockout animals
2015
Essential 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 response
2014
Semaphorin3a Promotes Advanced Diabetic Nephropathy
Aggarwal PK, Veron D, Thomas DB, Siegel D, Moeckel G, Kashgarian M, Tufro A. Semaphorin3a Promotes Advanced Diabetic Nephropathy. Diabetes 2014, 64: 1743-1759. PMID: 25475434, PMCID: PMC4407856, DOI: 10.2337/db14-0719.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsChromonesCollagen Type IVDiabetes Mellitus, ExperimentalDiabetic NephropathiesEnzyme-Linked Immunosorbent AssayGene Expression RegulationGene Knockdown TechniquesHumansIntegrin alphaVbeta3LamininMembrane ProteinsMiceMice, KnockoutMicrofilament ProteinsMicrotubule-Associated ProteinsMixed Function OxygenasesNerve Tissue ProteinsPodocytesProteinuriaReceptors, Cell SurfaceRenal InsufficiencySemaphorin-3AWT1 ProteinsXanthonesConceptsAdvanced diabetic nephropathyDiabetic nephropathyRenal insufficiencyDiffuse podocyte foot process effacementPodocyte foot process effacementSevere diabetic nephropathyCollagen IV accumulationPotential therapeutic targetFoot process effacementGlomerular nodulesKimmelstiel-WilsonRenal biopsyGlomerular filtration barrierNodular glomerulosclerosisDiabetic miceMassive proteinuriaNovel therapiesDisease outcomePathogenic factorsTargetable pathwaysTherapeutic targetProcess effacementBarrier abnormalitiesFunction miceNephropathyPodocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice
Veron D, Aggarwal PK, Velazquez H, Kashgarian M, Moeckel G, Tufro A. Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice. Journal Of The American Society Of Nephrology 2014, 25: 1814-1824. PMID: 24578128, PMCID: PMC4116059, DOI: 10.1681/asn.2013070752.Peer-Reviewed Original ResearchConceptsNodular glomerulosclerosisGain of functionEndothelial nitric oxide synthase knockout miceNitric oxide synthase knockout miceGlomerular basement membrane thickeningENOS-null miceSynthase knockout miceBasement membrane thickeningWild-type miceCollagen IVArteriolar hyalinosisGlomerular nodulesGlomerular VEGFKimmelstiel-WilsonPronounced albuminuriaCreatinine clearanceRenal failureDiabetic nephropathyENOS deficiencyMassive proteinuriaDiabetic milieuMembrane thickeningPodocyte effacementDeposition of lamininKnockout micePodocyte-associated talin1 is critical for glomerular filtration barrier maintenance
Tian X, Kim JJ, Monkley SM, Gotoh N, Nandez R, Soda K, Inoue K, Balkin DM, Hassan H, Son SH, Lee Y, Moeckel G, Calderwood DA, Holzman LB, Critchley DR, Zent R, Reiser J, Ishibe S. Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. Journal Of Clinical Investigation 2014, 124: 1098-1113. PMID: 24531545, PMCID: PMC3934159, DOI: 10.1172/jci69778.Peer-Reviewed Original ResearchConceptsNephrotic syndromeFoot process effacementLoss of talin1Glomerular filtration barrierGlomerular injuryMurine modelProcess effacementKidney's glomerular filtration barrierFiltration barrierGlomerular basement membraneSevere proteinuriaKidney failurePharmacologic inhibitionSyndromeBarrier maintenanceCalpain activityIntegrin activationEpithelial cellsPodocytesModest reductionΒ1 integrin activationBasement membranePathogenesisInjuryCytoskeletal protein talin1
2013
Early B-cell factor 1 is an essential transcription factor for postnatal glomerular maturation
Fretz JA, Nelson T, Velazquez H, Xi Y, Moeckel GW, Horowitz MC. Early B-cell factor 1 is an essential transcription factor for postnatal glomerular maturation. Kidney International 2013, 85: 1091-1102. PMID: 24172684, PMCID: PMC4006322, DOI: 10.1038/ki.2013.433.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAlbuminuriaAnimalsBlood Urea NitrogenCell DifferentiationCells, CulturedGene Expression Regulation, DevelopmentalGenotypeGlomerular Filtration RateKidney GlomerulusMice, 129 StrainMice, Inbred C57BLMice, KnockoutOrganogenesisPhenotypePodocytesSignal TransductionTime FactorsTrans-ActivatorsVascular Endothelial Growth Factor AConceptsEarly B-cell factor 1B cell factor 1Transcription factorsNovel roleTranscription factor early B cell factor 1Expression of Ebf1Essential transcription factorFactor 1Podocyte maturationMesenchymal progenitorsB cell maturationProper maturationBlood urea nitrogen levelsElevated blood urea nitrogen levelsWild-type control miceGlomerular filtration rateVascular endothelial growth factor AGlomerular maturationUrea nitrogen levelsGrowth factor ARenal developmentEBF1Factor AGlomerular developmentNephron maturation
2012
Role of dynamin, synaptojanin, and endophilin in podocyte foot processes
Soda K, Balkin DM, Ferguson SM, Paradise S, Milosevic I, Giovedi S, Volpicelli-Daley L, Tian X, Wu Y, Ma H, Son SH, Zheng R, Moeckel G, Cremona O, Holzman LB, De Camilli P, Ishibe S. Role of dynamin, synaptojanin, and endophilin in podocyte foot processes. Journal Of Clinical Investigation 2012, 122: 4401-4411. PMID: 23187129, PMCID: PMC3533561, DOI: 10.1172/jci65289.Peer-Reviewed Original ResearchConceptsRole of dynaminNormal embryonic developmentFiltration barrierSynaptic vesicle recyclingFoot process formationKidney filtration barrierGlomerular filtration barrierNeuronal synapse developmentDynamin's roleEndophilin 3Actin cytoskeletonActin dynamicsFunctional partnersDynamin 1Endophilin-1Embryonic developmentVesicle recyclingProtein networkKidney's glomerular filtration barrierSynapse developmentDynaminPodocyte foot processesNeuronal synapsesSynaptojaninEndophilinAcute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus
Veron D, Villegas G, Aggarwal PK, Bertuccio C, Jimenez J, Velazquez H, Reidy K, Abrahamson DR, Moeckel G, Kashgarian M, Tufro A. Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus. PLOS ONE 2012, 7: e40589. PMID: 22808199, PMCID: PMC3396653, DOI: 10.1371/journal.pone.0040589.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood PressureCells, CulturedDown-RegulationDoxycyclineEndotheliumFibronectinsGene Knockdown TechniquesIntegrin alphaVbeta3MiceModels, AnimalNeuropilin-1PhenotypePodocytesProtein BindingProteinuriaRenal InsufficiencyRNA, Small InterferingSignal TransductionVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2ConceptsAcute renal failureVEGF receptor 2Renal failureEndothelial cell swellingPodocyte VEGFUrine VEGFGlomerular filtration barrierLocal injuryPodocyte effacementGlomerular ultrastructureAdult miceDoxycycline exposureReceptor 2Knockdown micePodocyte cell lineControl valuesGlomeruliNeuropilin-1MiceVEGFProtein levelsCell swellingVEGF knockdownProteinuriaFiltration barrier
2011
Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression
Cheng H, Fan X, Moeckel GW, Harris RC. Podocyte COX-2 Exacerbates Diabetic Nephropathy by Increasing Podocyte (Pro)renin Receptor Expression. Journal Of The American Society Of Nephrology 2011, 22: 1240-1251. PMID: 21737546, PMCID: PMC3137572, DOI: 10.1681/asn.2010111149.Peer-Reviewed Original ResearchConceptsCOX-2 transgenic miceDiabetic nephropathyFoot process effacementCOX-2Transgenic miceGlomerular injuryReceptor expressionHigh glucoseRenin-angiotensin systemMesangial matrix expansionCOX-2 inhibitionWild-type miceCOX-2 inhibitorsCyclooxygenase-2 expressionGlomerular basement membraneStreptozotocin modelProgressive albuminuriaSegmental thickeningMesangial expansionDiabetic mellitusCell injuryAnimal modelsInjuryIncreased expressionNephropathyPodocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes
Veron D, Bertuccio CA, Marlier A, Reidy K, Garcia AM, Jimenez J, Velazquez H, Kashgarian M, Moeckel GW, Tufro A. Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia 2011, 54: 1227-1241. PMID: 21318407, PMCID: PMC3397150, DOI: 10.1007/s00125-010-2034-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternChromatography, High Pressure LiquidCreatinineDiabetes Mellitus, Type 1Diabetic NephropathiesDisease Models, AnimalEnzyme-Linked Immunosorbent AssayImmunohistochemistryMiceMice, TransgenicMicroscopy, Electron, TransmissionPodocytesPolymerase Chain ReactionSemaphorin-3ATandem Mass SpectrometryVascular Endothelial Growth Factor AConceptsDiabetic nephropathyNodular glomerulosclerosisDiabetic glomerulopathyMouse modelMassive proteinuriaExcessive vascular endothelial growth factorTransgenic miceStreptozotocin-induced mouse modelVascular endothelial growth factor overexpressionGlomerular basement membrane thickeningAdvanced diabetic glomerulopathyControl diabetic miceOnset of diabetesBasement membrane thickeningVascular endothelial growth factorType 1 diabetesGrowth factor overexpressionAdult transgenic miceEndothelial growth factorVEGF receptor 2Kimmelstiel-WilsonSystemic VEGFDiabetic micePathogenic roleRenal morphology
2009
Distinct Roles for Basal and Induced COX-2 in Podocyte Injury
Cheng H, Fan X, Guan Y, Moeckel GW, Zent R, Harris RC. Distinct Roles for Basal and Induced COX-2 in Podocyte Injury. Journal Of The American Society Of Nephrology 2009, 20: 1953-1962. PMID: 19643929, PMCID: PMC2736764, DOI: 10.1681/asn.2009010039.Peer-Reviewed Original ResearchMeSH KeywordsAlbuminuriaAnimalsAntibiotics, AntineoplasticApoptosisCell AdhesionCell Line, TransformedCell SurvivalCyclooxygenase 2DinoprostoneDoxorubicinGlomerulonephritisMaleMiceMice, Inbred StrainsMice, TransgenicPodocytesPuromycinReceptors, Prostaglandin EReceptors, ThromboxaneRNA, MessengerThromboxanesConceptsCyclooxygenase-2Thromboxane receptorCOX-2 knockout miceSelective deletionCOX-2 deletionInduced COX-2Receptor subtype 4COX-2 metabolitesFoot process effacementGlomerular injuryPodocyte injuryProstanoid receptorsAttenuated albuminuriaWild-type podocytesSubtype 4Transgenic miceProcess effacementTP antagonistPodocyte survivalInjuryMore prostaglandinsGenetic deletionMicePodocytesGreater expression
2008
β1 integrin expression by podocytes is required to maintain glomerular structural integrity
Pozzi A, Jarad G, Moeckel GW, Coffa S, Zhang X, Gewin L, Eremina V, Hudson BG, Borza DB, Harris RC, Holzman LB, Phillips CL, Fassler R, Quaggin SE, Miner JH, Zent R. β1 integrin expression by podocytes is required to maintain glomerular structural integrity. Developmental Biology 2008, 316: 288-301. PMID: 18328474, PMCID: PMC2396524, DOI: 10.1016/j.ydbio.2008.01.022.Peer-Reviewed Original ResearchConceptsEnd-stage renal failureStage renal failureGlomerular structural integrityWeeks of agePodocin-cre miceGlomerular basement membraneGlomerular filtration barrier integrityNormal glomerular basement membraneExpression of beta1Renal failureGlomerular pathologyFiltration barrier integrityProgressive podocyte lossPodocyte lossGlomerular filtrationΒ1 integrin expressionBarrier integrityPodocyte abnormalitiesHeteromeric receptorsCapillary loopsGlomerular capillary formationMiceIntegrin expressionExtracellular matrixPodocytes
2007
Puromycin Induces Reversible Proteinuric Injury in Transgenic Mice Expressing Cyclooxygenase-2 in Podocytes
Jo YI, Cheng H, Wang S, Moeckel GW, Harris RC. Puromycin Induces Reversible Proteinuric Injury in Transgenic Mice Expressing Cyclooxygenase-2 in Podocytes. Nephron 2007, 107: e87-e94. PMID: 17890881, DOI: 10.1159/000108653.Peer-Reviewed Original ResearchConceptsCOX-2 expressionCOX-2-specific inhibitorsCOX-2 mRNATransgenic miceFoot process effacementDay 3COX-2Process effacementEndogenous COX-2 mRNAImmunoreactive COX-2Progressive renal diseaseCOX-2 overexpressionFoot process fusionCyclooxygenase-2 inhibitorRenal diseaseGlomerular injurySignificant albuminuriaCyclooxygenase-2Further injuryReal-time PCRDay 1Nephrin mRNADay 10AlbuminuriaMiceOverexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury
Cheng H, Wang S, Jo YI, Hao CM, Zhang M, Fan X, Kennedy C, Breyer MD, Moeckel GW, Harris RC. Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury. Journal Of The American Society Of Nephrology 2007, 18: 551-559. PMID: 17202413, DOI: 10.1681/asn.2006090990.Peer-Reviewed Original ResearchConceptsCOX-2 expressionBALB/c miceFoot process effacementTransgenic miceC micePodocyte injuryProcess effacementCOX-2 transgenic miceImmunoreactive COX-2 expressionCOX-2 mRNA expressionNephrin promoterLong-term treatmentCOX-2 overexpressionTransgenic mouse kidneyCyclooxygenase-2 expressionWild-type miceWild-type littermatesCOX-2 mRNARenal injuryRenal ablationAdriamycin nephropathyMore albuminuriaAdriamycin administrationFurther injuryCOX-2