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Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation.
EBioMedicine 2019; 47:319-328E

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 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.

Authors+Show Affiliations

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden.Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden; Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.Institut National de la Sante et de la Recherche Medicale (INSERM), U1188, Université de La Réunion, France.Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France.Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institute of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France.Department of Nephrology, Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden. Electronic address: diana.karpman@med.lu.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31444145

Citation

Lopatko Fagerström, Ingrid, et al. "Blockade of the Kallikrein-kinin System Reduces Endothelial Complement Activation in Vascular Inflammation." EBioMedicine, vol. 47, 2019, pp. 319-328.
Lopatko Fagerström I, Ståhl AL, Mossberg M, et al. Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation. EBioMedicine. 2019;47:319-328.
Lopatko Fagerström, I., Ståhl, A. L., Mossberg, M., Tati, R., Kristoffersson, A. C., Kahn, R., ... Karpman, D. (2019). Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation. EBioMedicine, 47, pp. 319-328. doi:10.1016/j.ebiom.2019.08.020.
Lopatko Fagerström I, et al. Blockade of the Kallikrein-kinin System Reduces Endothelial Complement Activation in Vascular Inflammation. EBioMedicine. 2019;47:319-328. PubMed PMID: 31444145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation. AU - Lopatko Fagerström,Ingrid, AU - Ståhl,Anne-Lie, AU - Mossberg,Maria, AU - Tati,Ramesh, AU - Kristoffersson,Ann-Charlotte, AU - Kahn,Robin, AU - Bascands,Jean-Loup, AU - Klein,Julie, AU - Schanstra,Joost P, AU - Segelmark,Mårten, AU - Karpman,Diana, Y1 - 2019/08/20/ PY - 2019/07/02/received PY - 2019/08/05/revised PY - 2019/08/08/accepted PY - 2019/8/25/pubmed PY - 2019/8/25/medline PY - 2019/8/25/entrez KW - Complement KW - Endothelial microvesicles KW - Kidney KW - Kinin KW - Mouse KW - Vasculitis SP - 319 EP - 328 JF - EBioMedicine JO - EBioMedicine VL - 47 N2 - 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. SN - 2352-3964 UR - https://www.unboundmedicine.com/medline/citation/31444145/Blockade_of_the_kallikrein-kinin_system_reduces_endothelial_complement_activation_in_vascular_inflammation L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3964(19)30542-0 DB - PRIME DP - Unbound Medicine ER -