title: Globotriaosylsphingosine actions on human glomerular podocytes: implications for Fabry nephropathy.
abstract: BACKGROUND
  Transforming growth factor-β1 (TGF-β1) and the macrophage inhibitory factor receptor CD74 link the metabolic disorder with tissue injury in diabetic nephropathy. Fabry disease is an X-linked lysosomal glycosphingolipid storage disorder resulting from a deficient activity of α-galactosidase A that leads to proteinuric renal injury. However, the link between the metabolic abnormality and renal injury is poorly characterized. Globotriaosylsphingosine (lyso-Gb3) was recently identified as a bioactive molecule accumulating in Fabry disease. We hypothesized that lyso-Gb3 could modulate the release of secondary mediators of injury in glomerular podocytes and that recently described nephroprotective actions of vitamin D receptor activation in diabetic nephropathy may apply to lyso-Gb3.
  
  
  METHODS
  Real time RT-PCR, ELISA and Western blot were used to study the biological activity of lyso-Gb3 in cultured human podocytes and potential modulation by vitamin D receptor activation.
  
  
  RESULTS
  In human podocytes, lyso-Gb3 dose and time dependently increased the expression of TGF-β1, extracellular matrix proteins (fibronectin and type IV collagen) and CD74. TGF-β1 mediated lyso-Gb3 effects on extracellular matrix production. Vitamin D receptor activation with paricalcitol or calcitriol prevented the increase in TGF-β1, CD74 and extracellular matrix induced by lyso-Gb3.
  
  
  CONCLUSIONS
  Lyso-Gb3 may have a role in glomerular injury in Fabry disease by promoting the release of secondary mediators of glomerular injury common to diabetic nephropathy. These effects are prevented by paricalcitol, raising the issue of vitamin D receptor activation as potential adjunctive therapy in Fabry nephropathy.
authors.affiliation: Nefrología, Fundación Jiménez Díaz, Universidad Autonoma de Madrid and Instituto Reina Sofia de Investigaciones Nefrológicas-IRSIN, Madrid, Spain.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.forename: Susana
authors.initials: S
authors.lastname: Carrasco
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: José M
authors.initials: JM
authors.lastname: Valdivielso
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D000795:Fabry Disease / Q000188:drug therapy / Q000378:metabolism*; D006017:Glycolipids / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016326:Extracellular Matrix Proteins; D006017:Glycolipids; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D013107:Sphingolipids; D053773:Transforming Growth Factor beta1; C045084:invariant chain; C063288:globotriaosyl lysosphingolipid