Complement factor D is predominantly expressed in mesangial cells in focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and is associated with a poor kidney prognosis. Complement activation, including the alternative pathway, has been implicated in FSGS. Complement factor D (CFD), a key component of the alternative complement pathway, has been implicated in adriamycin (ADR)-induced nephropathy. However, its pathogenic cellular source within the glomerulus remains unclear. Our previous multi-omics analysis revealed increased CFD levels in FSGS kidneys and increased CFD expression in glomerular endothelial, mesangial, and parietal epithelial cells. Therefore, we investigated the intraglomerular localization of CFD in FSGS. Glomerular CFD immunostaining was scarcely detected in healthy control kidneys, whereas CFD signals were increased and predominantly localized to the mesangial areas in FSGS kidneys. In the kidneys of an ADR-induced nephropathy mouse model, CFD was predominantly localized to the mesangial areas and co-localized with fibronectin (FN)-positive glomerular areas. In cultured MES 13 mesangial cells, ADR increased CFD and FN expression, whereas Cfd knockdown attenuated ADR-induced FN accumulation. These findings identify mesangial cells as the predominant intraglomerular CFD-expressing cell type in FSGS, and suggest that mesangial CFD contributes to FN accumulation and sclerotic remodeling.