Journal Article

Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy

Nester, Carla M., Taylor, Amanda O., Smith, Richard J. H., Goicoechea de Jorge, Elena, Roberts, Sarah M., Zhang, Yuzhou, Nelson, Angela F. M., Sun, Mingyao, Slagle, Amanda K., Rodriguez de Cordoba, Santiago, Ghiringhelli Borsa, Nicolo, Jones, Michael B., Wang, Kai, Walls, William D., Meyer, Nicole C., Jalal, Diana I.

2025

Overview

Dysregulation of the alternative pathway of complement underlies the pathogenesis of C3 glomerulopathy (C3G). Because Factor H (FH) prevents excessive alternative pathway activity while Factor H-related protein 1 (FHR-1) is believed to enhance this response, we investigated the balance between FH and FHR-1 in C3G. To assess the role of FHR-1 in C3G pathogenicity, we used a multiplex ligation-dependent probe amplification to detect copy number variants in and enzyme linked immunosorbent assays to measure circulating protein levels in C3G patients compared to controls. Additionally, an C3b deposition assay was used to characterize the functional impact of FHR-1 on local complement activity. In this study, we confirm that copy number impacts C3G risk. In C3G patients with two copies of , the FHR-1:FH protein ratios are increased compared to controls; however, this increase is not disease specific. Rather, it is reflective of deteriorating renal function and was also observed in a second cohort of patients with chronic kidney disease from a variety of other causes. Functional studies showed that FHR-1 competes with FH to increase C3b deposition on mouse mesangial cell surfaces, an effect enhanced by heparan sulfate cleavage. Altogether, we show that as renal function declines, a change in the FHR-1:FH ratio combined with changes in heparan sulfate architecture increase complement activity. These findings suggest that complement activity may contribute to the chronic inflammation and progression of renal damage associated with chronic kidney disease.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Alternative pathway / Animals / Antibodies / Blood Proteins - genetics / Blood Proteins - metabolism / C3 glomerulopathy / chronic kidney disease / Complement Activation / Complement C3 - immunology / Complement C3 - metabolism / Complement C3b - immunology / Complement C3b - metabolism / Complement C3b Inactivator Proteins - genetics / Complement C3b Inactivator Proteins - metabolism / Complement component C3 / Complement Factor H - metabolism / Complement Pathway, Alternative / complement regulation / Copy number / DNA Copy Number Variations / Factor H / Female / FHR-1 / Genes / Glomerulonephritis, Membranoproliferative - immunology / Glomerulonephritis, Membranoproliferative - metabolism / Heparan sulfate / Heparan Sulfate - immunology / Heparan Sulfate - metabolism / Humans / Kidney diseases / Ligands / Male / Mice / Middle Aged / Pathogenesis / Pathogenicity / Proteins / Regulation / Renal function