Complement C5a and C5a receptor 1 mediates glomerular damage in focal segmental glomerulosclerosis

Background: Clinical data and animal models have provided compelling evidence supporting the pathogenic role of complement activation in the progression of focal segmental glomerulosclerosis (FSGS). However, the mechanisms underlying complement-induced podocyte injury and parietal epithelial cell (PEC) activation are not well understood. Methods: We evaluated glomerular C5aR1 (CD88) expression in FSGS patients and tested the effects of the C5aR1 antagonist (PMX205) in Adriamycin nephropathy mice. The effects on PECs and podocytes were evaluated following exposure to recombinant C5a or FSGS plasma, with or without the C5aR1 antagonist. Results: C5aR1 was overexpressed on PECs and podocytes in FSGS patients, with levels positively correlated with serum creatinine, the percentage of segmental glomerulosclerosis, and the prognosis of refractory nephrotic syndrome. In Adriamycin nephropathy mice, the C5aR1 antagonist significantly attenuated proteinuria, blood urea nitrogen levels, and the percentage of segmental and global glomerulosclerosis. It also alleviated PEC activation and proliferation, and mitigated podocyte loss. Moreover, glomerular IgM deposits were reduced, followed by decreased deposits of C3d and C5b-9. In vitro, PECs exposed to recombinant C5a exhibited upregulated expression of CD44 and Notch1, along with increased secretion of COL4A2. Podocytes exposed to FSGS plasma showed impaired cell viability and downregulation of synaptopodin, effects that were reversed by the C5aR1 antagonist. Conclusions: These findings highlight the pathogenic role of the complement system in the development of FSGS through the C5a-C5aR1 axis on podocytes and PECs. The C5aR1 antagonist represents a promising therapeutic intervention for FSGS patients.