Factor H related proteins modulate complement activation on kidney cells.
complement
factor H
factor H–related protein
glomerulus
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
12
09
2021
revised:
04
07
2022
accepted:
27
07
2022
pubmed:
6
9
2022
medline:
24
11
2022
entrez:
5
9
2022
Statut:
ppublish
Résumé
Complement activation at a particular location is determined by the balance of activating and inhibitory proteins. Factor H is a key regulator of the alternative pathway of complement, and genetic or acquired impairments in Factor H are associated with glomerular injury. The human Factor H-related proteins (FHRs) comprise a family of five proteins that are structurally related to Factor H. Variations in the genes or expression levels of the FHRs are also associated with glomerular disease, although the mechanisms of glomerular protection/injury are incompletely understood. To explore the role of the FHRs on complement regulation/dysregulation in the kidney, we expressed and purified recombinant murine FHRs (FHRs A, B, C and E). These four distinct FHRs contain binding regions with high amino acid sequence homology to binding regions within Factor H, but we observed different interactions of the FHRs with Factor H binding ligands, including heparin and C3d. There was differential binding of the FHRs to the resident kidney cell types (mesangial, glomerular endothelial, podocytes, and tubular epithelial). All four FHRs caused complement dysregulation on kidney cell surfaces in vitro, although the magnitude of the effect differed among the FHRs and also varied among the different kidney cells. However, only FHR E caused glomerular complement dysregulation when injected in vivo but did not exacerbate injury when injected into mice with ischemic acute kidney injury, an alternative pathway-mediated model. Thus, our experiments demonstrate that the FHRs have unique, and likely context-dependent, effects on the different cell types within the kidney.
Identifiants
pubmed: 36063874
pii: S0085-2538(22)00692-5
doi: 10.1016/j.kint.2022.07.035
pmc: PMC9691546
mid: NIHMS1834437
pii:
doi:
Substances chimiques
CFH protein, human
0
Complement Factor H
80295-65-4
Complement System Proteins
9007-36-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1331-1344Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK125823
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116073
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001082
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK113586
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076690
Pays : United States
Organisme : Wellcome Trust
ID : 212252/Z/18/Z
Pays : United Kingdom
Informations de copyright
Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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