Blockade of the kallikrein-kinin system reduces endothelial complement activation in vascular inflammation

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. (C) 2019 The Authors. Published by Elsevier B.V. Funding Agencies|Swedish Research CouncilSwedish Research Council [K2015-99X-22877-01-6, 2017-01920]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [2015.0320]; Torsten Soderberg Foundation; Skane Centre of Excellence in Health; Crown Princess Lovisas Society for Child Care; Konung Gustaf V:s 80-arsfond; Alfred Osterlund Foundation; Wallenberg Center for Molecular Medicine; Swedish Rheumatism Association; Anna-Greta Crafoord Foundation; Greta and Johan Kocks Foundation; Samariten Foundation; Fanny Ekdahl foundation; Jerring foundation; Fondation pour la Recherche MedicaleFondation pour la Recherche Medicale [DEQ20170336759]; Ingrid Asp Foundation; IngaBritt och Arne Lundbergs Research Foundation; Region Skane; Thelma Zoegas Foundation