title: Vitronectin dictates intraglomerular fibrinolysis in immune-mediated glomerulonephritis.
abstract: During human glomerulonephritis, the severity of injuries correlates with glomerular fibrin deposits, which are tightly regulated by the intraglomerular fibrinolytic system. Here, we evaluated the role of vitronectin (VTN; also known as complement S protein), the principal cofactor of the plasminogen activator inhibitor-1 (PAI-1), in a mouse model of acute glomerulonephritis. We found that in mice subjected to nephrotoxic serum, the absence of VTN resulted in a lower glomerular PAI-1 activity and a higher glomerular fibrinolytic activity. Challenged VTN(-/-) mice displayed significantly less fibrin deposits, proteinuria, and renal failure than their wild-type counterparts. Notably, this protective effect afforded by VTN deficiency was still observed after a C3 depletion. Finally, the injection of VTN(+/+) serum in VTN(-/-) mice induced the glomerular deposition of VTN, increased PAI-1 deposition, decreased glomerular fibrinolytic activity, and aggravated glomerular injury. As in mice, abundant glomerular VTN deposits were also observed in patients with severe glomerulonephritis. Here, we show that plasma-exchange therapy, admittedly beneficial in this clinical context, induces a significant depletion in circulating VTN, which might modulate PAI-1 activity locally and accelerate the clearance of fibrin deposits in the glomeruli. Collectively, these results demonstrate that VTN exerts a deleterious role independently from complement, by directing PAI-dependent fibrinolysis in the glomerular compartment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S 702, Université Pierre et Marie Curie, Hôpital Tenon, Paris, France. laurent.mesnard@tnn.aphp.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.forename: Cédric
authors.initials: C
authors.lastname: Rafat
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hertig
authors.forename: Dominique
authors.initials: D
authors.lastname: Cathelin
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Xu-Dubois
authors.forename: Chantal
authors.initials: C
authors.lastname: Jouanneau
authors.forename: Alexandre Castro
authors.initials: AC
authors.lastname: Keller
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.forename: Maria C
authors.initials: MC
authors.lastname: Leite-de-Moraes
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005342:Fibrinolysis / Q000502:physiology*; D005786:Gene Expression Regulation; D050533:Glomerular Basement Membrane / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism*; D007074:Immunoglobulin G / Q000276:immunology / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D051437:Renal Insufficiency / Q000378:metabolism; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D019096:Vitronectin