Journal article
Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy
Frontiers in immunology, Vol.16, 1589674
05/16/2025
DOI: 10.3389/fimmu.2025.1589674
PMCID: PMC12122740
PMID: 40453077
Abstract
Introduction: 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.
Methods: To assess the role of FHR-1 in C3G pathogenicity, we used a multiplex ligation-dependent probe amplification to detect copy number variants in CFHR3-CFHR1 and enzyme linked immunosorbent assays to measure circulating protein levels in C3G patients compared to controls. Additionally, an in vitro C3b deposition assay was used to characterize the functional impact of FHR-1 on local complement activity.
Results: In this study, we confirm that CFHR3-CFHR1 copy number impacts C3G risk. In C3G patients with two copies of CFHR3-CFHR1, 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.
Discussion: 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.
Details
- Title: Subtitle
- Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy
- Creators
- Amanda K. Slagle - University of IowaNicolo Ghiringhelli Borsa - University of IowaKai Wang - University of Iowa, BiostatisticsAmanda O. Taylor - University of IowaNicole C. Meyer - University of IowaMichael B. Jones - University of IowaWilliam D. Walls - University of IowaAngela F. M. Nelson - University of IowaSarah M. Roberts - University of IowaMingyao Sun - University of IowaElena Goicoechea de Jorge - Consejo Superior de Investigaciones CientíficasSantiago Rodriguez de Cordoba - Consejo Superior de Investigaciones CientíficasDiana I. Jalal - University of IowaCarla M. Nester - University of IowaYuzhou Zhang - University of IowaRichard J. H. Smith - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Frontiers in immunology, Vol.16, 1589674
- DOI
- 10.3389/fimmu.2025.1589674
- PMID
- 40453077
- PMCID
- PMC12122740
- NLM abbreviation
- Front Immunol
- ISSN
- 1664-3224
- eISSN
- 1664-3224
- Publisher
- FRONTIERS MEDIA SA
- Grant note
- National Institutes of Health: R01 DK110023, R01 HL134738, R01 DK133240, T32 AI007485
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Institutes of Health (grant numbers R01 DK110023 (CMN, RJHS), R01 HL134738 (DJ), R01 DK133240 (RJHS, DJ) and T32 AI007485 (KJ)).
- Language
- English
- Date published
- 05/16/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biostatistics; Nephrology; Otolaryngology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984824297702771
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