Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice.
Peritoneal fibrosis (PF) is an important complication of peritoneal dialysis therapy. The present study was performed to examine the mechanisms of PF in view of the plasminogen activator (PA)/plasmin/matrix metalloproteinase (MMP) cascade. PF was induced in tissue-type PA (tPA) deficient mice and wild-type mice by intraperitoneal injection of chlorhexidine gluconate. Mice were killed on day 21, and tissue samples were taken. Histopathological studies were performed. Plasmin activity, gelatinases activity, and the levels of tPA, transforming growth factor-beta1 (TGF-beta1), and MMP-2 mRNA were determined. Protein levels of MMP-3, tissue inhibitor of metalloproteinases (TIMP)-1, -2, and -3, phospho-Smad3, membrane-type 1 (MT1)-MMP, and MT3-MMP were also studied. On day 21, tPA +/+ mice showed severe PF, whereas tPA -/- mice showed milder change. Submesothelial basement membranes were dissolved in tPA +/+ mice while they were relatively preserved in tPA -/- mice. The levels of macrophage infiltration, staining for alpha-smooth muscle actin (alpha-SMA) and collagen type III, and vascular density were all significantly lower in tPA -/- mice than in tPA +/+ mice. The levels of plasmin activity, pro- and active MMP-2, mRNA expression of tPA and TGF-beta1, and phospho-Smad3 protein were also lower in tPA -/- mice. No difference was observed between the two groups concerning the protein levels of MMP-3, TIMP-1, TIMP-2, TIMP-3, MT1-MMP, or MT3-MMP. These results indicate that the presence of tPA enhances inflammation, angiogenesis, and fibrogenesis in the peritoneum of the PF model mice. Activation of the PA/plasmin/MMP cascade may play a pivotal role in the pathogenesis of PF.
Kurata
Kei
K
Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Maruyama
Shoichi
S
Kato
Sawako
S
Sato
Waichi
W
Yamamoto
Jun-Ichiro
J
Ozaki
Takenori
T
Nitta
Atsumi
A
Nabeshima
Toshitaka
T
Morita
Yoshiki
Y
Mizuno
Masashi
M
Ito
Yasuhiko
Y
Yuzawa
Yukio
Y
Matsuo
Seiichi
S
D000818:Animals; D002710:Chlorhexidine / Q000031:analogs & derivatives; D005341:Fibrinolysin / Q000378:metabolism; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000378:metabolism; D000090023:Metallothionein 3; D051379:Mice; D018345:Mice, Knockout; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000172:deficiency*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D012333:RNA, Messenger; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; C010882:chlorhexidine gluconate; D002710:Chlorhexidine