Vitronectin dictates intraglomerular fibrinolysis in immune-mediated glomerulonephritis

Autor(es):Mostrar menos -

Mesnard, Laurent ^{[1, 2]} ; Rafat, Cedric ^{[1, 2]} ; Vandermeersch, Sophie ^[1] ; Hertig, Alexandre ^{[1, 2]} ; Cathelin, Dominique ^[1] ; Xu-Dubois, Yi-Chun ^[1] ; Jouanneau, Chantal ^[1] ; Keller, Alexandre Castro ^{[3, 4]} ; Ribeil, Jean-Antoine ^{[4, 5]} ; Leite-de-Moraes, Maria C. ^[4] ; Rondeau, Eric ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Paris 06, INSERM, UMR S702, Hop Tenon, F-75020 Paris - France

^[2] Univ Paris 06, Hop Tenon, APHP, F-75020 Paris - France

^[3] Univ Fed Sao Paulo, Div Nephrol, Sao Paulo - Brazil

^[4] Hop Necker Enfants Malad, CNRS, UMR 8147, Paris - France

^[5] Hop Necker Enfants Malad, APHP, Fac Med Rene Descartes, Dept Biotherapie, Paris - France

• Tipo de documento: Artigo Científico
• Fonte: FASEB JOURNAL; v. 25, n. 10, p. 3543-3553, OCT 2011.
• Citações Web of Science: 6

Resumo

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.org (AU)

• Processo FAPESP: 07/07120-0 - O papel de células T invariantes natural killer no desenvolvimento de glomerulonefrite: mecanismos e perspectivas
• Beneficiário: Alexandre de Castro Keller
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores