Vitronectin dictates intraglomerular fibrinolysis in immune-mediated glomerulonephritis

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.-Mesnard, L., Rafat, C., Vandermeersch, S., Hertig, A., Cathelina, D., Xu-Dubois, Y. -C., Jouanneau, C., Castro Keller, A., Ribeil, J. -A., Leite-de-Moraes, M. C., Rondeau, E. Vitronectin dictates intraglomerular fibrinolysis in immune-mediated glomerulonephritis. FASEB J. 25, 3543-3553 (2011). www.fasebj.orgInstitut National de la Sante et de la Recherche Medicale (INSERM)Faculte de Medecine Pierre et Marie CurieAcademie de MedecineEuropean Renal Association-European Dialysis and Transplant Association (ERA-EDTA)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Paris 06, INSERM, UMR S702, Hop Tenon, F-75020 Paris, FranceUniv Paris 06, Hop Tenon, APHP, F-75020 Paris, FranceHop Necker Enfants Malad, CNRS, UMR 8147, Paris, FranceHop Necker Enfants Malad, APHP, Fac Med Rene Descartes, Dept Biotherapie, Paris, FranceUniversidade Federal de São Paulo, Div Nephrol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Nephrol, São Paulo, BrazilFAPESP: 2007/07120-0CNPq: 501848/2009-6Web of Scienc