Lyso-Gb3 activates Notch1 in human podocytes

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 p...

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Bibliographic Details
Published in:Human molecular genetics 2015-10, Vol.24 (20), p.5720-5732
Main Authors: Sanchez-Niño, Maria D, Carpio, Daniel, Sanz, Ana Belen, Ruiz-Ortega, Marta, Mezzano, Sergio, Ortiz, Alberto
Format: Article
Language:English
Subjects:
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
Receptor, Notch1 - drug effects
Receptor, Notch1 - genetics
RNA, Small Interfering
Serrate-Jagged Proteins
Signal Transduction
Sphingolipids - pharmacology
Transcription Factor HES-1
Up-Regulation
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddv291