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Selective Binding of Heparin/Heparan Sulfate Oligosaccharides to Factor H and Factor H-Related Proteins: Therapeutic Potential for C3 Glomerulopathies
Journal article   Open access   Peer reviewed

Selective Binding of Heparin/Heparan Sulfate Oligosaccharides to Factor H and Factor H-Related Proteins: Therapeutic Potential for C3 Glomerulopathies

Markus A Loeven, Marissa L Maciej-Hulme, Cansu Yanginlar, Melanie C Hubers, Edwin Kellenbach, Mark de Graaf, Toin H van Kuppevelt, Jack Wetzels, Ton J Rabelink, Richard J H Smith, …
Frontiers in immunology, Vol.12, pp.676662-676662
2021
DOI: 10.3389/fimmu.2021.676662
PMCID: PMC8416517
PMID: 34489931
url
https://doi.org/10.3389/fimmu.2021.676662View
Published (Version of record) Open Access

Abstract

Complement dysregulation is characteristic of the renal diseases atypical hemolytic uremic syndrome (aHUS) and complement component 3 glomerulopathy (C3G). Complement regulatory protein Factor H (FH) inhibits complement activity, whereas FH-related proteins (FHRs) lack a complement regulatory domain. FH and FHRs compete for binding to host cell glycans, in particular heparan sulfates (HS). HS is a glycosaminoglycan with an immense structural variability, where distinct sulfation patterns mediate specific binding of proteins. Mutations in FH, FHRs, or an altered glomerular HS structure may disturb the FH : FHRs balance on glomerular endothelial cells, thereby leading to complement activation and the subsequent development of aHUS/C3G. In this study, we aimed to identify specific HS structures that could specifically compete off FHRs from HS glycocalyx (HS ), without interfering with FH binding. FH/FHR binding to human conditionally immortalized glomerular endothelial cells (ciGEnCs) and HS purified from ciGEnC glycocalyx was assessed. HS modifications important for FH/FHR binding to HS were analyzed using selectively desulfated heparins in competition with purified HS . We further assessed effects of heparinoids on FHR1- and FHR5-mediated C3b deposition on ciGEnCs. In the presence of C3b, binding of FH, FHR1 and FHR5 to ciGEnCs was significantly increased, whereas binding of FHR2 was minimal. FHR1 and 5 competitively inhibited FH binding to HS , leading to alternative pathway dysregulation. FHR1 and FHR5 binding was primarily mediated by N-sulfation while FH binding depended on N-, 2-O- and 6-O-sulfation. Addition of 2-O-desulfated heparin significantly reduced FHR1- and FHR5-mediated C3b deposition on ciGEnCs. We identify 2-O-desulfated heparin derivatives as potential therapeutics for C3G and other diseases with dysregulated complement.
 Atypical Hemolytic Uremic Syndrome - blood Cells, Cultured Complement Activation Complement C3b - metabolism Complement Factor H - metabolism Complement System Proteins - metabolism Endothelial Cells - metabolism Heparin - analogs & derivatives Heparin - metabolism Heparin - pharmacology Heparitin Sulfate - metabolism Humans Kidney Glomerulus - metabolism Protein Binding - drug effects Signal Transduction - drug effects

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