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Abstract: TH-PO787

Role of Colony-Stimulating Factor-1 Receptor in Driving Parietal Epithelial Cell Activation in Focal Segmental Glomerulosclerosis

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Amaya-Garrido, Ana, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Doladé Masot, Nuria, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Manonelles, Anna, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • Varela, Cristian, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Codina Sanchez, Sergi, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • Couceiro Monteagudo, Carlos, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain
  • Cruzado, Josep M., Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Catalunya, Spain
  • Sola, Anna, Institut d'Investigacio Biomedica de Bellvitge, Barcelona, Catalunya, Spain

Group or Team Name

  • Endogenous Renal Regeneration, Inflammation and Aging (Nephrology and Renal Transplantation Group).
Background

Parietal epithelial cells (PECs) are renal progenitor cells similar to bone marrow stem cell niches. In focal segmental glomerulosclerosis (FSGS), activated PECs contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts through its specific receptor, CSF-1R, and has been implicated in various glomerular diseases. However, its role in PEC activation is still unknown. In this study, we studied the CSF-1/CSF-1R pathway in dysfunctional activation of PECs in FSGS.

Methods

CSF-1R expression was assessed in FSGS patient biopsies and in adriamycin (ADR)-induced FSGS mouse model. ADR-induced animals were further treated with specific CSF-1R inhibitors, GW2580 or Ki20227 (n=5-7). CSF-1R expression, localization in the glomerulus and its relevance to glomerulosclerosis were examined, as well as de novo CD44 formation and its correlation with the ERK1/2 pathway. Human kidney progenitor cells were treated with CSF-1 (n=6/group) to observe migration and proliferation changes and to identify potential key interactors of CSF-1 through RNAseq. Genes of interest were validated in the FSGS model.

Results

CSF-1R was upregulated in PECs and podocytes in FSGS biopsies. In vitro, results showed that PECs constitutively expressed CSF-1R. CSF-1 treatment induced CSF-1R upregulation and transcriptional changes in genes associated with PEC activation. CSF-1/CSF-1R activated the ERK1/2 pathway, upregulated CD44 while both ERK and CSF-1-R inhibitors reduced CD44 expression. CSF-1 promoted PEC proliferation and migration while suppressing podocyte differentiation. These results were validated in the ADR-induced FSGS model. Treatment with specific CSF-1R inhibitors demonstrated strong therapeutic effects. CSF-1 also promoted interferon (IFN)-related gene transcription in human PECs.

Conclusion

This study provides the first evidence of the involvement of the CSF-1/CSF-1R pathway in PEC activation in FSGS and suggests potential therapeutic use of CSF-1R inhibitors in FSGS treatment.