SMPDL3b modulates insulin receptor signaling in diabetic kidney disease
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Nature Publishing Group
Abstract
Sphingomyelin 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).
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Animals, Antigens, cd, Caveolin 1, Cell line, Cell membrane, Ceramides, Cyclic nucleotide phosphodiesterases, type 3, Diabetic nephropathies, Disease models, animal, Female, Humans, Insulin, Male, Mice, Mice, knockout, Podocytes, Protein isoforms, Receptor, insulin, Signal transduction, Sphingomyelin phosphodiesterase, Treatment outcome, Mus, Alanine aminotransferase, Ceramide 1 phosphate, Genomic dna, Immunoglobulin enhancer binding protein, Insulin receptor, Leptin receptor, Mammalian target of rapamycin, Mitogen activated protein kinase kinase 1, Mitogen activated protein kinase kinase 2, Phosphatidylinositol 3 kinase, Protein kinase b, Sphingomyelin phosphodiesterase acid like 3b, Triacylglycerol, Tumor necrosis factor, Unclassified drug, Cav1 protein, human, Cav1 protein, mouse, Ceramide, Ceramide 1-phosphate, Insr protein, human, Isoprotein, Leukocyte antigen, Phosphodiesterase iii, Smpdl3b protein, human, Sphingomyelinase-like phosphodiesterase 3b, mouse, Chemoreception, Diabetes, Disease, Enzyme, Enzyme activity, Gene expression, Hormone, Lipid, Membrane, Plasma, Protein, Albuminuria, Animal experiment, Animal model, Animal tissue, Apoptosis, Article, Controlled study, Creatinine urine level, Diabetic complication, Diabetic nephropathy, Electron microscopy, Enzyme deficiency, Enzyme linked immunosorbent assay, Flow cytometry, Genotype, Glomerulus basement membrane, Glycemic control, Human, Human cell, Immunohistochemistry, Immunoprecipitation, Innate immunity, Insulin signaling, Kidney cortex, Kidney hypertrophy, Lipid raft, Liquid chromatography-mass spectrometry, Mouse, Mtor signaling, Nonhuman, Phenotype, Plasmid, Podocyte, Polymerase chain reaction, Protein expression, Protein phosphorylation, Sequence analysis, Transient transfection, Upregulation, Western blotting, Animal, Cytology, Disease model, Genetics, Knockout mouse, Metabolism, Pathology