Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis.
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.
Nomura
Keiko
K
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Liu
Ning
N
Nagai
Kojiro
K
Hasegawa
Takamichi
T
Kobayashi
Ikei
I
Nogaki
Fumiaki
F
Tanaka
Misa
M
Arai
Hidenori
H
Fukatsu
Atsushi
A
Kita
Toru
T
Ono
Takahiko
T
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity; D001777:Blood Coagulation / Q000502:physiology*; D015153:Blotting, Western; D005165:Factor V / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000378:metabolism; D013997:Time Factors
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000911:Antibodies, Monoclonal; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D011422:Propionates; D044464:Receptor, PAR-2; D005165:Factor V; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015951:Factor Xa