title: Lyso-Gb3 activates Notch1 in human podocytes.
abstract: Podocyte injury is an early feature of Fabry nephropathy, but the molecular mechanisms of podocyte injury are poorly understood. Lyso-Gb3 accumulates in serum in Fabry disease and increases extracellular matrix synthesis in podocytes. We explored the contribution of Notch1 signaling, a mediator of podocyte injury, to lyso-Gb3-elicited responses in cultured human podocytes. At clinically relevant concentrations, lyso-Gb3 activates podocyte Notch1 signaling, resulting in increased active Notch1 and HES1, a canonical Notch transcriptional target. A γ-secretase inhibitor or specific Notch1 small interfering RNA (siRNA) inhibited HES1 upregulation in response to lyso-Gb3. Notch1 siRNA or γ-secretase inhibition also prevented the lyso-Gb3-induced upregulation of Notch1, Notch ligand Jagged1 and chemokine (MCP1, RANTES) expression. Notch siRNA prevented the activation of nuclear factor kappa B (NFκB), and NFκB activation contributed to Notch1-mediated inflammatory responses as the NFκB inhibitor, parthenolide, prevented lyso-Gb3-induced chemokine upregulation. Notch1 also mediates fibrogenic responses in podocytes as Notch siRNA prevented lyso-Gb3 upregulation of fibronectin mRNA. Supporting the clinical relevance of cell culture findings, active Notch1, Jagged1 and HES1 were observed in Fabry kidney biopsies. Lyso-Gb3 elicited similar responses in mouse kidney. In conclusion, lyso-Gb3 promotes Notch1-mediated inflammatory and fibrogenic responses in podocytes that may contribute to Fabry nephropathy.
authors.affiliation: IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.affiliation: Unidad de Nefrología, Instituto de Medicina, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.affiliation: IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Unidad de Nefrología, Instituto de Medicina, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.affiliation: IIS-Fundacion Jimenez Diaz, School of Medicine, UAM, Madrid, Spain, IRSIN, Madrid, Spain, REDINREN, Madrid, Spain and aortiz@fjd.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002478:Cells, Cultured; D000795:Fabry Disease / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005353:Fibronectins / Q000235:genetics; D006017:Glycolipids / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000187:drug effects / Q000235:genetics*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013107:Sphingolipids / Q000494:pharmacology*; D000072056:Transcription Factor HES-1; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D005353:Fibronectins; D006017:Glycolipids; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D013107:Sphingolipids; D000072056:Transcription Factor HES-1; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497761:NOTCH1 protein, human; C063288:globotriaosyl lysosphingolipid; C078493:HES1 protein, human