Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation
(2019) In EBioMedicine 47. p.319-328- Abstract
Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation. Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist. Findings: Vasculitis... (More)
Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation. Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist. Findings: Vasculitis patient plasma had significantly more C3- and C9-positive endothelial microvesicles than controls. Perfusion of patient acute-phase plasma samples over glomerular endothelial cells induced the release of significantly more complement-positive microvesicles, in comparison to remission or control plasma. Complement activation on endothelial microvesicles was reduced by kinin B1- and B2-receptor antagonists or by C1-inhibitor (the main inhibitor of the classical pathway and the KKS). Likewise, perfusion of glomerular endothelial cells with C1-inhibitor-depleted plasma induced the release of complement-positive microvesicles, which was significantly reduced by kinin-receptor antagonists or C1-inhibitor. Mice with nephrotoxic serum-induced glomerulonephritis exhibited significantly reduced glomerular C3 deposition when treated with a B1-receptor antagonist. Interpretation: Excessive complement deposition on the endothelium will promote endothelial injury and the release of endothelial microvesicles. This study demonstrates that blockade of the KKS can reduce complement activation and thereby the inflammatory response on the endothelium. Funding: Full details are provided in the Acknowledgements/Funding section.
(Less)
- author
- Lopatko Fagerström, Ingrid
LU
; Ståhl, Anne lie
LU
; Mossberg, Maria
LU
; Tati, Ramesh
LU
; Kristoffersson, Ann Charlotte
LU
; Kahn, Robin
LU
; Bascands, Jean Loup
; Klein, Julie
; Schanstra, Joost P.
; Segelmark, Mårten
LU
and Karpman, Diana
LU
(Less) - organization
- publishing date
- 2019-08-20
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Complement, Endothelial microvesicles, Kidney, Kinin, Mouse, Vasculitis
- in
- EBioMedicine
- volume
- 47
- pages
- 319 - 328
- publisher
- Elsevier
- external identifiers
-
- scopus:85070898653
- pmid:31444145
- ISSN
- 2352-3964
- DOI
- 10.1016/j.ebiom.2019.08.020
- language
- English
- LU publication?
- yes
- id
- 3966028e-e0db-4049-aee4-fd7316acfa62
- date added to LUP
- 2019-09-05 09:40:47
- date last changed
- 2024-05-14 21:28:25
@article{3966028e-e0db-4049-aee4-fd7316acfa62,
abstract = {{<p>Background: The complement and kallikrein-kinin systems (KKS) are activated during vascular inflammation. The aim of this study was to investigate if blockade of the KKS can affect complement activation on the endothelium during inflammation. Methods: Complement deposition on endothelial microvesicles was assayed in vasculitis patient plasma samples and controls. Plasma was perfused over glomerular endothelial cells and complement deposition assayed by flow cytometry. The effect of the kinin system was assessed using kinin receptor antagonists and C1-inhibitor. The in vivo effect was assessed in kidney sections from mice with nephrotoxic serum-induced glomerulonephritis treated with a kinin receptor antagonist. Findings: Vasculitis patient plasma had significantly more C3- and C9-positive endothelial microvesicles than controls. Perfusion of patient acute-phase plasma samples over glomerular endothelial cells induced the release of significantly more complement-positive microvesicles, in comparison to remission or control plasma. Complement activation on endothelial microvesicles was reduced by kinin B1- and B2-receptor antagonists or by C1-inhibitor (the main inhibitor of the classical pathway and the KKS). Likewise, perfusion of glomerular endothelial cells with C1-inhibitor-depleted plasma induced the release of complement-positive microvesicles, which was significantly reduced by kinin-receptor antagonists or C1-inhibitor. Mice with nephrotoxic serum-induced glomerulonephritis exhibited significantly reduced glomerular C3 deposition when treated with a B1-receptor antagonist. Interpretation: Excessive complement deposition on the endothelium will promote endothelial injury and the release of endothelial microvesicles. This study demonstrates that blockade of the KKS can reduce complement activation and thereby the inflammatory response on the endothelium. Funding: Full details are provided in the Acknowledgements/Funding section.</p>}},
author = {{Lopatko Fagerström, Ingrid and Ståhl, Anne lie and Mossberg, Maria and Tati, Ramesh and Kristoffersson, Ann Charlotte and Kahn, Robin and Bascands, Jean Loup and Klein, Julie and Schanstra, Joost P. and Segelmark, Mårten and Karpman, Diana}},
issn = {{2352-3964}},
keywords = {{Complement; Endothelial microvesicles; Kidney; Kinin; Mouse; Vasculitis}},
language = {{eng}},
month = {{08}},
pages = {{319--328}},
publisher = {{Elsevier}},
series = {{EBioMedicine}},
title = {{Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation}},
url = {{http://dx.doi.org/10.1016/j.ebiom.2019.08.020}},
doi = {{10.1016/j.ebiom.2019.08.020}},
volume = {{47}},
year = {{2019}},
}