Lyso-Gb3 activates Notch1 in human podocytes

Hum Mol Genet. 2015 Oct 15;24(20):5720-32. doi: 10.1093/hmg/ddv291. Epub 2015 Jul 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Calcium-Binding Proteins / genetics
  • Cells, Cultured
  • Fabry Disease / metabolism
  • Fabry Disease / physiopathology
  • Female
  • Fibronectins / genetics
  • Glycolipids / pharmacology*
  • Homeodomain Proteins / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Mice
  • Podocytes / drug effects
  • Podocytes / metabolism*
  • RNA, Small Interfering
  • Receptor, Notch1 / drug effects
  • Receptor, Notch1 / genetics*
  • Serrate-Jagged Proteins
  • Signal Transduction*
  • Sphingolipids / pharmacology*
  • Transcription Factor HES-1
  • Up-Regulation


  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Fibronectins
  • Glycolipids
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • NOTCH1 protein, human
  • RNA, Small Interfering
  • Receptor, Notch1
  • Serrate-Jagged Proteins
  • Sphingolipids
  • Transcription Factor HES-1
  • globotriaosyl lysosphingolipid
  • HES1 protein, human