title: Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis.
abstract: Crescentic glomerulonephritis is characterized by glomerular fibrin deposition, and experimental crescentic glomerulonephritis has been shown to be fibrin-dependent. Net fibrin deposition is a balance between activation of the coagulation system causing glomerular fibrin deposition and fibrin removal by the plasminogen-plasmin (fibrinolytic) system. Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis by inhibiting plasminogen activators and has effects on leukocyte recruitment and matrix deposition. To test the hypothesis that the presence of PAI-1 and its levels were a determinant of injury in crescentic glomerulonephritis, accelerated anti-glomerular basement membrane glomerulonephritis was induced in mice genetically deficient in PAI-1 (PAI-1 -/-), PAI-1 heterozygotes (PAI-1 +/-), and mice engineered to overexpress PAI-1 (PAI-1 tg). Compared with strain-matched genetically normal animals, PAI-1 -/- mice with glomerulonephritis developed fewer glomerular crescents, less glomerular fibrin deposition, fewer infiltrating leukocytes, and less renal collagen accumulation at day 14 of disease. The reduction in disease persisted at day 28, when injury had become more established. In contrast, mice overexpressing the PAI-1 gene (PAI-1 tg), that have basal plasma and renal PAI-1 levels several times, normal developed increased glomerular crescent formation, more glomerular fibrin deposition, increased numbers of infiltrating leukocytes, and more renal collagen at both time points. These studies demonstrate that PAI-1 is a determinant of glomerular fibrin deposition and renal injury in crescentic glomerulonephritis.
authors.affiliation: Centre for Inflammatory Diseases, and Department of Medicine, Monash Medical Centre, Monash University, Clayton, Victoria, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Yao Z
authors.initials: YZ
authors.lastname: Kong
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Piers
authors.initials: P
authors.lastname: Davenport
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Edgtton
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: Peter G
authors.initials: PG
authors.lastname: Tipping
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003094:Collagen / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005921:Glomerulonephritis / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007958:Leukocyte Count; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin; D003094:Collagen