Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation.
BACKGROUND
Fibrin deposition and mesangial cell proliferation are frequently observed in the active type of mesangioproliferative glomerulonephritis. Coagulation factors, such as factor V and factor Xa are colocalized with fibrin in the mesangial areas in active type of IgA nephropathy with mesangial cell proliferation. In this study, therefore, we studied the role of factor Xa and its receptor, protease-activated receptor 2 (PAR2) in mesangial cell proliferation and fibrin deposition, and examined ant-proliferative effects of a specific factor Xa inhibitor, DX-9065a, in cultured human mesangial cells.


METHODS
To examine the effect of DX-9065a on the factor Xa-induced proliferation of cultured human mesangial cells, we measured thymidine incorporation and cell numbers. We also examined the effect of DX-9065a on extracellular regulated kinase (ERK) activation and fibrin production induced by factor Xa in human mesangial cells.


RESULTS
Factor Xa increased [(3)H]-thymidine incorporation and cell numbers in a dose-dependent manner in mesangial cells, which was inhibited by DX-9065a. DX-9065a also suppressed factor Xa-triggered fibrin deposition on mesangial cell surface. Factor Xa induced the activation of ERK in mesangial cells and this activation was also completely inhibited by DX-9065a, but not inhibited by PAR1 antagonist. Factor Xa-induced cell proliferation and ERK activation were inhibited by PD98059.


CONCLUSIONS
There results suggest that factor Xa can induce mesangial cell proliferation through the activation of ERK via PAR2 in mesangial cells and that PAR2 may play a crucial role in the cell proliferation induced by factor Xa. Our results implicate that DX-9065a may be a promising agent to regulate proliferation of mesangial cellss and inhibit the coagulation process in mesangium.
Tanaka
Misa
M
Division of Nephrology, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Arai
Hidenori
H
Liu
Ning
N
Nogaki
Fumiaki
F
Nomura
Keiko
K
Kasuno
Kenji
K
Oida
Emi
E
Kita
Toru
T
Ono
Takahiko
T
D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015951:Factor Xa / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology*; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000502:physiology; D044464:Receptor, PAR-2 / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D001549:Benzamides; C403255:FR 171113; D009281:Naphthalenes; D011422:Propionates; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D013844:Thiazoles; D053778:Thiazolidines; D048049:Extracellular Signal-Regulated MAP Kinases; D015951:Factor Xa