Summary
Fibrin formation within the glomeruli has been observed in various forms of human
and experimental glomerulonephritis and it may play an important role in progressive
glomerular injury. Furthermore it has been hypothesized that glomerular fibrin deposition
may occur through activation of either the intrinsic or extrinsic coagulation pathway.
It has been demonstrated that a procoagulant activity (PCA) which is compatible with
tissue factor is present in the glomeruli and becomes increased in human proliferative
glomerulonephritis and in animal models of nephritis. Tissue factor pathway inhibitor
(TFPI) regulates the extrinsic 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 whether 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 using a specific antibody. Cultured HMC showed the production
of TFPI. Immunoblot analysis revealed 40 kD protein of TFPI. The concentration of
TFPI was significantly increased following the incubation with thrombin and heparin,
including low molecular weight heparin, in a dose- and time-dependent manner. However,
fetal calf serum, phorbol myristate acetate, lipopolysaccharide, IL-1β and tissue
factor did not stimulate TFPI synthesis. Our data show that cultured HMC have the
ability to produce TFPI which inhibits fibrin formation. It is possible that thrombin-induced
enhancement of TFPI synthesis may be caused by the autoregulatory system of blood
coagulation and that with heparin it may represent another anticoagulatory effect
of heparin.
