Cargando…
Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface
INTRODUCTION: C3 glomerulopathies (C3G) are ultra-rare complement-mediated diseases that lead to end-stage renal disease (ESRD) within 10 years of diagnosis in ~50% of patients. Overactivation of the alternative pathway (AP) of complement in the fluid phase and on the surface of the glomerular endot...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947773/ https://www.ncbi.nlm.nih.gov/pubmed/36846022 http://dx.doi.org/10.3389/fimmu.2022.1073802 |
_version_ | 1784892634498596864 |
---|---|
author | Pisarenka, Sofiya Meyer, Nicole C. Xiao, Xue Goodfellow, Renee Nester, Carla M. Zhang, Yuzhou Smith, Richard J. H. |
author_facet | Pisarenka, Sofiya Meyer, Nicole C. Xiao, Xue Goodfellow, Renee Nester, Carla M. Zhang, Yuzhou Smith, Richard J. H. |
author_sort | Pisarenka, Sofiya |
collection | PubMed |
description | INTRODUCTION: C3 glomerulopathies (C3G) are ultra-rare complement-mediated diseases that lead to end-stage renal disease (ESRD) within 10 years of diagnosis in ~50% of patients. Overactivation of the alternative pathway (AP) of complement in the fluid phase and on the surface of the glomerular endothelial glycomatrix is the underlying cause of C3G. Although there are animal models for C3G that focus on genetic drivers of disease, in vivo studies of the impact of acquired drivers are not yet possible. METHODS: Here we present an in vitro model of AP activation and regulation on a glycomatrix surface. We use an extracellular matrix substitute (MaxGel) as a base upon which we reconstitute AP C3 convertase. We validated this method using properdin and Factor H (FH) and then assessed the effects of genetic and acquired drivers of C3G on C3 convertase. RESULTS: We show that C3 convertase readily forms on MaxGel and that this formation was positively regulated by properdin and negatively regulated by FH. Additionally, Factor B (FB) and FH mutants impaired complement regulation when compared to wild type counterparts. We also show the effects of C3 nephritic factors (C3Nefs) on convertase stability over time and provide evidence for a novel mechanism of C3Nef-mediated C3G pathogenesis. DISCUSSION: We conclude that this ECM-based model of C3G offers a replicable method by which to evaluate the variable activity of the complement system in C3G, thereby offering an improved understanding of the different factors driving this disease process. |
format | Online Article Text |
id | pubmed-9947773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99477732023-02-24 Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface Pisarenka, Sofiya Meyer, Nicole C. Xiao, Xue Goodfellow, Renee Nester, Carla M. Zhang, Yuzhou Smith, Richard J. H. Front Immunol Immunology INTRODUCTION: C3 glomerulopathies (C3G) are ultra-rare complement-mediated diseases that lead to end-stage renal disease (ESRD) within 10 years of diagnosis in ~50% of patients. Overactivation of the alternative pathway (AP) of complement in the fluid phase and on the surface of the glomerular endothelial glycomatrix is the underlying cause of C3G. Although there are animal models for C3G that focus on genetic drivers of disease, in vivo studies of the impact of acquired drivers are not yet possible. METHODS: Here we present an in vitro model of AP activation and regulation on a glycomatrix surface. We use an extracellular matrix substitute (MaxGel) as a base upon which we reconstitute AP C3 convertase. We validated this method using properdin and Factor H (FH) and then assessed the effects of genetic and acquired drivers of C3G on C3 convertase. RESULTS: We show that C3 convertase readily forms on MaxGel and that this formation was positively regulated by properdin and negatively regulated by FH. Additionally, Factor B (FB) and FH mutants impaired complement regulation when compared to wild type counterparts. We also show the effects of C3 nephritic factors (C3Nefs) on convertase stability over time and provide evidence for a novel mechanism of C3Nef-mediated C3G pathogenesis. DISCUSSION: We conclude that this ECM-based model of C3G offers a replicable method by which to evaluate the variable activity of the complement system in C3G, thereby offering an improved understanding of the different factors driving this disease process. Frontiers Media S.A. 2023-01-18 /pmc/articles/PMC9947773/ /pubmed/36846022 http://dx.doi.org/10.3389/fimmu.2022.1073802 Text en Copyright © 2023 Pisarenka, Meyer, Xiao, Goodfellow, Nester, Zhang and Smith https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Pisarenka, Sofiya Meyer, Nicole C. Xiao, Xue Goodfellow, Renee Nester, Carla M. Zhang, Yuzhou Smith, Richard J. H. Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface |
title | Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface |
title_full | Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface |
title_fullStr | Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface |
title_full_unstemmed | Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface |
title_short | Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface |
title_sort | modeling c3 glomerulopathies: c3 convertase regulation on an extracellular matrix surface |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947773/ https://www.ncbi.nlm.nih.gov/pubmed/36846022 http://dx.doi.org/10.3389/fimmu.2022.1073802 |
work_keys_str_mv | AT pisarenkasofiya modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface AT meyernicolec modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface AT xiaoxue modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface AT goodfellowrenee modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface AT nestercarlam modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface AT zhangyuzhou modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface AT smithrichardjh modelingc3glomerulopathiesc3convertaseregulationonanextracellularmatrixsurface |