Endothelial-derived complement factor D contributes to endothelial dysfunction in malignant nephrosclerosis via local complement activation.
Alternative pathway
Complement factor D
Endothelial cells
Local complement
Malignant nephrosclerosis
Journal
Hypertension research : official journal of the Japanese Society of Hypertension
ISSN: 1348-4214
Titre abrégé: Hypertens Res
Pays: England
ID NLM: 9307690
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
11
06
2022
accepted:
20
03
2023
revised:
24
12
2022
medline:
6
7
2023
pubmed:
16
5
2023
entrez:
15
5
2023
Statut:
ppublish
Résumé
Malignant nephrosclerosis is a thrombotic microangiopathy associated with abnormal local activation of the complement alternative pathway (AP). However, the mechanism underlying local AP activation is not fully understood. We hypothesized that complement factor D (CFD) secreted by endothelial cells triggers vascular dysfunction in malignant nephrosclerosis via local complement activation. We investigated the deposition of CFD in human kidney biopsy tissues and the function of endothelial-derived CFD in endothelial cell cultures. Immunofluorescence microscopy and laser microdissection-targeted mass spectrometry revealed significant deposition of CFD in the kidneys of patients with malignant nephrosclerosis. Conditionally immortalized human glomerular endothelial cells (CiGEnCs) continuously expressed and secreted CFD in vitro. CFD knockdown in CiGEnCs by small interfering RNA reduced local complement activation and attenuated the upregulation of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), von Willebrand factor (VWF), and endothelin-1 (ET-1) induced by Ang II. The expression of CFD in CiGEnCs was significantly higher than that in other types of microvascular endothelial cells. Our findings suggest that (i) glomerular endothelial cells are an important source of local renal CFD, (ii) endothelial-derived CFD can activate the local complement system, and (iii) endothelial-derived CFD mediates endothelial dysfunction, which may play a role in the pathogenesis of malignant nephrosclerosis.
Identifiants
pubmed: 37188751
doi: 10.1038/s41440-023-01300-3
pii: 10.1038/s41440-023-01300-3
pmc: PMC10184087
doi:
Substances chimiques
Complement Factor D
EC 3.4.21.46
Complement System Proteins
9007-36-7
Intercellular Adhesion Molecule-1
126547-89-5
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1759-1770Informations de copyright
© 2023. The Author(s).
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