期刊
KIDNEY INTERNATIONAL
卷 102, 期 6, 页码 1331-1344出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.07.035
关键词
complement; factor H; factor H-related protein; glomerulus
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [P30DK116073]
- National Institutes of Health (NIH)/National Center for Advancing Translational Sciences Colorado CTSI grant [UL1TR001082]
- NIH [R01DK076690, R01DK113586, R01CA225840, R01DK125823]
This study demonstrates that the Factor H-related proteins have unique effects on different cell types within the kidney, with FHR E causing glomerular complement dysregulation in vivo. This has important implications for understanding the pathogenesis of glomerular diseases.
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.
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