TISSUE FACTOR PATHWAY INHIBITOR PRODUCTION BY HUMAN MESANGIAL CELLS IN CULTURE

Fibrin formation within the glomeruli has been observed in various for ms of human and experimental glomerulonephritis and it may play an imp ortant role in progressive glomerular injury. Furthermore it has been hypothesized that glomerular fibrin deposition may occur through activ ation of either the intrinsic or extrinsic coagulation pathway. It has been demonstrated that a procoagulant activity (PCA) which is compati ble with tissue factor is present in the glomeruli and becomes increas ed in human proliferative glomerulonephritis and in animal models of n ephritis. Tissue factor pathway inhibitor (TFPI) regulates the extrins ic pathway of blood coagulation through its ability to inhibit tissue factor activity. TFPI is present in plasma and in platelets, and it is now thought to be produced mainly by endothelial cells. We examined w hether human mesangial cells (HMC) could produce TFPI and attempted to clarify regulatory factors which affect TFPI production. Cultured HMC were used and TFPI in the cell supernatants was measured by ELISA usi ng a specific antibody. Cultured HMC showed the production of TFPI. Im munoblot analysis revealed 40 kD protein of TFPI. The concentration of TFPI was significantly increased following the incubation with thromb in and heparin, including low molecular weight heparin, in a dose- and time-dependent manner. However, fetal calf serum, phorbol myristate a cetate, lipopolysaccharide, IL-1 beta and tissue factor did not stimul ate TFPI synthesis. Our data show that cultured HMC have the ability t o produce TFPI which inhibits fibrin formation. It is possible that th rombin-induced enhancement of TFPI synthesis may be caused by the auto regulatory system of blood coagulation and that with heparin it may re present another anticoagulatory effect of heparin.