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: Laurent Mesnard, Cédric Rafat, Sophie Vandermeersch, Alexandre Hertig, Dominique Cathelin, Yi-Chun Xu-Dubois, Chantal Jouanneau, Alexandre Castro Keller, Jean-Antoine Ribeil, Maria C Leite-de-Moraes, Eric Rondeau
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 25 Issue 10 Pg. 3543-53 (Oct 2011) ISSN: 1530-6860 [Electronic] United States
• PMID: 21764994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin G
• Serpin E2
• Serpine2 protein, mouse
• Vitronectin

Topics

• Animals
• Enzyme-Linked Immunosorbent Assay
• Fibrinolysis (physiology)
• Gene Expression Regulation
• Glomerular Basement Membrane (immunology)
• Glomerulonephritis (immunology, metabolism)
• Immunoglobulin G (immunology, toxicity)
• Mice
• Mice, Knockout
• Renal Insufficiency (metabolism)
• Serpin E2 (genetics, metabolism)
• Vitronectin (genetics, metabolism)