Vitronectin dictates intraglomerular fibrinolysis in immune-mediated glomerulonephritis

• Autor(a) principal: Mesnard, Laurent
• Data de Publicação: 2011
• Outros Autores: Rafat, Cedric, Vandermeersch, Sophie, Hertig, Alexandre, Cathelin, Dominique, Xu-Dubois, Yi-Chun, Jouanneau, Chantal, Keller, Alexandre Castro [UNIFESP], Ribeil, Jean-Antoine, Leite-de-Moraes, Maria C., Rondeau, Eric
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://dx.doi.org/10.1096/fj.11-180752; http://repositorio.unifesp.br/handle/11600/34073
• topic: complement system; mouse model; PAI-1; Kidney

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