Tissue factor initiates the extrinsic coagulation pathway by activating
coagulation factor X to
factor Xa, and
factor V is a cofactor for the
prothrombin activation by
factor Xa. As
factor Xa is known to promote the proliferation of mesangial cells in culture, the roles of the coagulation pathway and
factor Xa were studied in an animal model of mesangioproliferative
glomerulonephritis (MsPGN). MsPGN was induced in Wistar rats by an
intravenous injection of anti-Thy 1.1
monoclonal antibody, OX-7. To clarify the role of
factor Xa in MsPGN, a specific
factor Xa inhibitor,
DX-9065a, was injected intravenously at 2.5 or 10 mg/kg at the same time as OX-7, and kidney involvement was assessed by immunohistological analyses. We also examined p44/42
mitogen-activated
protein (MAP)
kinase activation. Time-course study revealed that expressions of
tissue factor,
factor V, and
protease-activated receptor 2 (PAR2) were peaked on day 3, followed by
factor X accumulation and mesangial proliferation.
DX-9065a treatment significantly ameliorated
proteinuria in a dose-dependent manner on day 8. Histological analyses showed a significant reduction in the size of glomeruli, the total number of glomerular cells, and crescent formation by
DX-9065a treatment. Macrophage infiltration, which was rapidly observed on day 1 in disease control rats was not inhibited on days 1-3 by
DX-9065a treatment, however it was suppressed on days 5-8. The deposition of
fibrin, the number of
PCNA-positive cells, and phosphorylation of p44/42 MAP
kinase were markedly increased in the disease control group, whereas they were significantly reduced in the treatment group.
Tissue factor and
factor V induction may accelerate MsPGN through the activation and accumulation of
factor X via proinflammatory and procoagulant mechanisms, and the inhibition of
factor Xa would be a promising method to regulate the disease process.