Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy
IntroductionDysregulation 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 b...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-05-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1589674/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849727846040207360 |
|---|---|
| author | Amanda K. Slagle Amanda K. Slagle Nicolo Ghiringhelli Borsa Kai Wang Amanda O. Taylor Nicole C. Meyer Michael B. Jones William D. Walls Angela F. M. Nelson Sarah M. Roberts Mingyao Sun Elena Goicoechea de Jorge Santiago Rodriguez de Cordoba Diana I. Jalal Diana I. Jalal Carla M. Nester Yuzhou Zhang Richard J. H. Smith Richard J. H. Smith |
| author_facet | Amanda K. Slagle Amanda K. Slagle Nicolo Ghiringhelli Borsa Kai Wang Amanda O. Taylor Nicole C. Meyer Michael B. Jones William D. Walls Angela F. M. Nelson Sarah M. Roberts Mingyao Sun Elena Goicoechea de Jorge Santiago Rodriguez de Cordoba Diana I. Jalal Diana I. Jalal Carla M. Nester Yuzhou Zhang Richard J. H. Smith Richard J. H. Smith |
| author_sort | Amanda K. Slagle |
| collection | DOAJ |
| description | IntroductionDysregulation 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.MethodsTo 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.ResultsIn 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.DiscussionAltogether, 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. |
| format | Article |
| id | doaj-art-ba7f6a8b0a7b47f6aa4a56a69bf4397a |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-ba7f6a8b0a7b47f6aa4a56a69bf4397a2025-08-20T03:09:44ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15896741589674Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathyAmanda K. Slagle0Amanda K. Slagle1Nicolo Ghiringhelli Borsa2Kai Wang3Amanda O. Taylor4Nicole C. Meyer5Michael B. Jones6William D. Walls7Angela F. M. Nelson8Sarah M. Roberts9Mingyao Sun10Elena Goicoechea de Jorge11Santiago Rodriguez de Cordoba12Diana I. Jalal13Diana I. Jalal14Carla M. Nester15Yuzhou Zhang16Richard J. H. Smith17Richard J. H. Smith18Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesGraduate PhD Program in Immunology, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesDepartment of Biostatistics, College of Public Health, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesDepartment of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesCentro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, SpainCentro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, SpainDepartment of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesCenter for Comprehensive Access and Delivery Research and Evaluation, Iowa City VA Health Care System, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesGraduate PhD Program in Immunology, Carver College of Medicine, University of Iowa, Iowa, IA, United StatesIntroductionDysregulation 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.MethodsTo 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.ResultsIn 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.DiscussionAltogether, 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1589674/fullFactor HFHR-1complement regulationC3 glomerulopathychronic kidney disease |
| spellingShingle | Amanda K. Slagle Amanda K. Slagle Nicolo Ghiringhelli Borsa Kai Wang Amanda O. Taylor Nicole C. Meyer Michael B. Jones William D. Walls Angela F. M. Nelson Sarah M. Roberts Mingyao Sun Elena Goicoechea de Jorge Santiago Rodriguez de Cordoba Diana I. Jalal Diana I. Jalal Carla M. Nester Yuzhou Zhang Richard J. H. Smith Richard J. H. Smith Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy Frontiers in Immunology Factor H FHR-1 complement regulation C3 glomerulopathy chronic kidney disease |
| title | Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy |
| title_full | Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy |
| title_fullStr | Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy |
| title_full_unstemmed | Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy |
| title_short | Factor H-related 1 and heparan sulfate architecture contribute to complement dysregulation in C3 glomerulopathy |
| title_sort | factor h related 1 and heparan sulfate architecture contribute to complement dysregulation in c3 glomerulopathy |
| topic | Factor H FHR-1 complement regulation C3 glomerulopathy chronic kidney disease |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1589674/full |
| work_keys_str_mv | AT amandakslagle factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT amandakslagle factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT nicologhiringhelliborsa factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT kaiwang factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT amandaotaylor factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT nicolecmeyer factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT michaelbjones factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT williamdwalls factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT angelafmnelson factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT sarahmroberts factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT mingyaosun factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT elenagoicoecheadejorge factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT santiagorodriguezdecordoba factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT dianaijalal factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT dianaijalal factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT carlamnester factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT yuzhouzhang factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT richardjhsmith factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy AT richardjhsmith factorhrelated1andheparansulfatearchitecturecontributetocomplementdysregulationinc3glomerulopathy |