SMPDL3b modulates insulin receptor signaling in diabetic kidney disease

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dc.contributor.authorMitrofanova, Alla V.
dc.contributor.authorMallela, Shamroop Kumar
dc.contributor.authorDucasa, Gloria Michelle
dc.contributor.authorYoo, Tae-hyun
dc.contributor.authorRosenfeld-Gur, Eden
dc.contributor.authorZelnik, Iris Daphne
dc.contributor.authorMolina, Judith David
dc.contributor.authorVarona-Santos, Javier T.
dc.contributor.authorGe, Mengyuan
dc.contributor.authorSloan, Alexis J.
dc.contributor.authorKim, Jin-ju
dc.contributor.authorPedigo, Christopher E.
dc.contributor.authorBryn, Jonathan
dc.contributor.authorVolosenco, Ion
dc.contributor.authorFaul, Christian
dc.contributor.authorZeidan, Youssef H.
dc.contributor.authorGarcia Hernandez, C.
dc.contributor.authorMéndez, Armando J.
dc.contributor.authorLeibiger, Ingo B.
dc.contributor.authorBurke, George William
dc.contributor.authorFuterman, Anthony H.
dc.contributor.authorBarisoni, Laura M.C.
dc.contributor.authorIshimoto, Yu
dc.contributor.authorInagi, Reiko
dc.contributor.authorMerscher, Sandra M.
dc.contributor.authorFornoni, Alessia
dc.contributor.departmentRadiation Oncology
dc.contributor.facultyFaculty of Medicine (FM)
dc.contributor.institutionAmerican University of Beirut
dc.date.accessioned2025-01-24T12:12:23Z
dc.date.available2025-01-24T12:12:23Z
dc.date.issued2019
dc.description.abstractSphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD. © 2019, The Author(s).
dc.identifier.doihttps://doi.org/10.1038/s41467-019-10584-4
dc.identifier.eid2-s2.0-85067607456
dc.identifier.pmid31217420
dc.identifier.urihttp://hdl.handle.net/10938/32744
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.ispartofNature Communications
dc.sourceScopus
dc.subjectAnimals
dc.subjectAntigens, cd
dc.subjectCaveolin 1
dc.subjectCell line
dc.subjectCell membrane
dc.subjectCeramides
dc.subjectCyclic nucleotide phosphodiesterases, type 3
dc.subjectDiabetic nephropathies
dc.subjectDisease models, animal
dc.subjectFemale
dc.subjectHumans
dc.subjectInsulin
dc.subjectMale
dc.subjectMice
dc.subjectMice, knockout
dc.subjectPodocytes
dc.subjectProtein isoforms
dc.subjectReceptor, insulin
dc.subjectSignal transduction
dc.subjectSphingomyelin phosphodiesterase
dc.subjectTreatment outcome
dc.subjectMus
dc.subjectAlanine aminotransferase
dc.subjectCeramide 1 phosphate
dc.subjectGenomic dna
dc.subjectImmunoglobulin enhancer binding protein
dc.subjectInsulin receptor
dc.subjectLeptin receptor
dc.subjectMammalian target of rapamycin
dc.subjectMitogen activated protein kinase kinase 1
dc.subjectMitogen activated protein kinase kinase 2
dc.subjectPhosphatidylinositol 3 kinase
dc.subjectProtein kinase b
dc.subjectSphingomyelin phosphodiesterase acid like 3b
dc.subjectTriacylglycerol
dc.subjectTumor necrosis factor
dc.subjectUnclassified drug
dc.subjectCav1 protein, human
dc.subjectCav1 protein, mouse
dc.subjectCeramide
dc.subjectCeramide 1-phosphate
dc.subjectInsr protein, human
dc.subjectIsoprotein
dc.subjectLeukocyte antigen
dc.subjectPhosphodiesterase iii
dc.subjectSmpdl3b protein, human
dc.subjectSphingomyelinase-like phosphodiesterase 3b, mouse
dc.subjectChemoreception
dc.subjectDiabetes
dc.subjectDisease
dc.subjectEnzyme
dc.subjectEnzyme activity
dc.subjectGene expression
dc.subjectHormone
dc.subjectLipid
dc.subjectMembrane
dc.subjectPlasma
dc.subjectProtein
dc.subjectAlbuminuria
dc.subjectAnimal experiment
dc.subjectAnimal model
dc.subjectAnimal tissue
dc.subjectApoptosis
dc.subjectArticle
dc.subjectControlled study
dc.subjectCreatinine urine level
dc.subjectDiabetic complication
dc.subjectDiabetic nephropathy
dc.subjectElectron microscopy
dc.subjectEnzyme deficiency
dc.subjectEnzyme linked immunosorbent assay
dc.subjectFlow cytometry
dc.subjectGenotype
dc.subjectGlomerulus basement membrane
dc.subjectGlycemic control
dc.subjectHuman
dc.subjectHuman cell
dc.subjectImmunohistochemistry
dc.subjectImmunoprecipitation
dc.subjectInnate immunity
dc.subjectInsulin signaling
dc.subjectKidney cortex
dc.subjectKidney hypertrophy
dc.subjectLipid raft
dc.subjectLiquid chromatography-mass spectrometry
dc.subjectMouse
dc.subjectMtor signaling
dc.subjectNonhuman
dc.subjectPhenotype
dc.subjectPlasmid
dc.subjectPodocyte
dc.subjectPolymerase chain reaction
dc.subjectProtein expression
dc.subjectProtein phosphorylation
dc.subjectSequence analysis
dc.subjectTransient transfection
dc.subjectUpregulation
dc.subjectWestern blotting
dc.subjectAnimal
dc.subjectCytology
dc.subjectDisease model
dc.subjectGenetics
dc.subjectKnockout mouse
dc.subjectMetabolism
dc.subjectPathology
dc.titleSMPDL3b modulates insulin receptor signaling in diabetic kidney disease
dc.typeArticle

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