#5466 CSF-1R SYSTEM ACTIVATES PARIETAL EPITHELIAL CELLS LEADING TO FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is the most common glomerular cause leading to end-stage kidney disease. Actual treatment of primary FSGS by immunosuppressive agents presents inconsistent results. Thus, new innovative strategies different from those used date taking into consideration podocyte renewal maintenance or even complementary immunosuppression are needed. In FSGS, parietal epithelial cells (PECs) switch an activated phenotype (aPECs) in response damage promoting glomerulosclerosis. Colony-stimulating factor (CSF-1) a hematopoietic growth that acts via its specific receptor, tyrosine kinase receptor CSF-1R. CSF-1 has been detected sera renal biopsies patients with complications, including attributing their role presence macrophage but not cells. The potential cellular molecular mechanisms involved also unknown. this work, we evaluated implication CSF-1/CSF-1R axis pathogenesis as pharmacological target point using CSF-1R inhibitors. Specifically, focused on modulation PECS activation de novo production CD44 preservation loss. Method We driver adriamycin-induced nephropathy (ADR) mice, main experimental model study human FSGS. To end, treated ADR-animals inhibitors, GW2580 Ki20227 (n = 5-7 group). determined expression localization glomerulus tissue triple immunofluorescence (WT-1, SSeCks CSF-1R) relevance (PAS pro-fibrotic genes), determination formation correlation ERK1/2 pathway immunohistochemistry (IH). WT-1 IH aPECS tuff Claudin-1 SSeCkS markers. Finally, isolated progenitor without 6/group) identify key interactors RNAseq. validated genes interest model. Results observed constitutively control mice significantly increased ADR-treated specifically podocytes (WT1) PECs (SSeCks), confirmed mRNA expression. showed important events sclerotic collagen was reversed inhibitors (p<0.001). reflected inhibitor-dependent function recovery use reduction proteinuria increase filtration rate found positive staining both Bowman's capsule inner accompanied activation. reduced percentage glomeruli production. Remarkably, depletion preserved very similar levels non-treated animals For RNAseq results, 227 differentially expressed (considering criterion probability differential >0.9 |M| > 1) were subjected enrichment analysis. top significant gene ontology terms mainly interferon-induced genes. Genes model, showing ADR compared controls alleviated Conclusion propose novel therapeutic strategy FSGS-associated pathology based inhibition CSF1-R activity having impact reducing aPECs, glomerulosclerosis, proteinuria, improving preserving podocyte-progenitor phenotype, thus, against damage.