Tissue factor initiates glomerular fibrin deposition and promotes major histocompatibility complex class II expression in crescentic glomerulonephritis.
Increased glomerular tissue factor (TF) expression is associated with glomerular fibrin deposition and renal failure in human and experimental crescentic glomerulonephritis (GN). However, the in vivo functional contribution of TF to the development of glomerular fibrin deposition, crescent formation, and renal failure in GN has not been established. The contribution of TF to fibrin deposition and renal injury was studied in a rabbit model of crescentic GN in which glomerular macrophage infiltration, augmented TF expression, and fibrin deposition are prominent. Administration of anti-TF antibody inhibited glomerular TF activity in nephritic glomeruli by 96%, without affecting macrophage accumulation or systemic indices of coagulation. Anti-TF antibody significantly reduced glomerular fibrin deposition (fibrin scores, 0.43 +/- 0.10 (treated) and 1.40 +/- 0.19 (control); P < 0.0005), crescent formation (0.33 +/- 0.05 (treated) and 1.0 +/- 0.06 (control); P < 0.0005), and development of renal failure (serum creatinine, 168 +/- 22 mumol/l (treated) and 267 +/- 35 mumol/l (control); P < 0.04). This was associated with significant reduction in proteinuria (1189 +/- 277 mg/24 hours (treated) and 2060 +/- 336 mg/24 hours (control); P < 0.03) and expression of MHC class II antigen in glomeruli (1.25 +/- 0.41 (treated) and 2.83 +/- 0.53 (control); P < 0.03) and in tubules and interstitial areas. These data demonstrate that TF is the major in vivo initiator of fibrin deposition in crescentic GN. The reduction in proteinuria and glomerular major histocompatibility class II antigen expression by TF inhibition suggests that TF may also activate other mediators that contribute to glomerular injury.
Erlich
J H
JH
Department of Medicine, Monash University, Clayton, Victoria, Australia.
Holdsworth
S R
SR
Tipping
P G
PG
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001777:Blood Coagulation / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism*; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D018796:Immunoconjugates / Q000008:administration & dosage; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011507:Proteinuria / Q000188:drug therapy; D011817:Rabbits; D051437:Renal Insufficiency / Q000188:drug therapy; D013925:Thromboplastin / Q000502:physiology*
D000906:Antibodies; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D005337:Fibrin; D013925:Thromboplastin