RENAL EXPRESSION OF TISSUE FACTOR PATHWAY INHIBITOR AND EVIDENCE FOR A ROLE IN CRESCENTIC GLOMERULONEPHRITIS IN RABBITS

Tissue factor pathway inhibitor (TFPI) was demonstrated in the kidneys of normal rabbits and in a crescentic model of glomerulonephritis (GN ), where fibrin is a key mediator of injury. In normal kidneys, TFPI w as expressed in glomeruli, in intrarenal arteries and;the interstitial capillary network. Evidence for TFPI synthesis in vivo was provided b y in situ demonstration of TFPI mRNA in glomeruli and intrarenal vesse ls and by biosynthetic labeling of TFPI released from glomeruli in vit ro. In fibrin-dependent crescentic GN, glomerular TFPI synthesis and e xpression was initially decreased (TFPI antigen at 24 h, 7.5+/-0.7 ng/ 10(3) glomeruli; normal, 11.1+/-0.9 ng/10(3) glomeruli, P < 0.02) and subsequently returned to normal values. Plasma TFPI levels increased p rogressively throughout the evolution of disease. In vivo inhibition o f TFPI using an anti-TFPI antibody during the development of GN signif icantly increased glomerular fibrin deposition (GFD) and exacerbated r enal impairment. Infusion of recombinant human TFPI significantly redu ced development of GFD (fibrin scores, TFPI treated 0.82+/-0.11, contr ol 1.49+/-0.14, P < 0.01), proteinuria and renal impairment. This data indicates that TFPI is synthesized and expressed in normal glomeruli and is down regulated in the early response to glomerular injury. Endo genous glomerular TFPI and treatment with recombinant TFPI reduces GFD and injury in fibrin dependent GN. TFPI has the potential to be of th erapeutic benefit in the management of fibrin dependent human GN.