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

Autor: Loeven MA; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Maciej-Hulme ML; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Yanginlar C; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Hubers MC; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Kellenbach E; Biochemical Technical Support Aspen Oss, Oss, Netherlands., de Graaf M; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., van Kuppevelt TH; Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Wetzels J; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Rabelink TJ; Department of Nephrology and Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands., Smith RJH; Departments of Internal Medicine and Otolaryngology, Carver College of Medicine, Iowa City, IA, United States., van der Vlag J; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2021 Aug 18; Vol. 12, pp. 676662. Date of Electronic Publication: 2021 Aug 18 (Print Publication: 2021).
DOI: 10.3389/fimmu.2021.676662
Abstrakt: 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 Glx ), without interfering with FH binding. FH/FHR binding to human conditionally immortalized glomerular endothelial cells (ciGEnCs) and HS Glx purified from ciGEnC glycocalyx was assessed. HS modifications important for FH/FHR binding to HS Glx were analyzed using selectively desulfated heparins in competition with purified HS Glx . 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 Glx , 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.
Competing Interests: Author EK was employed by company Aspen API. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Loeven, Maciej-Hulme, Yanginlar, Hubers, Kellenbach, de Graaf, van Kuppevelt, Wetzels, Rabelink, Smith and van der Vlag.)
Databáze: MEDLINE
Externí odkaz: