Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice

Kei Kurata, Shoichi Maruyama, Sawako Kato, Waichi Sato, Jun Ichiro Yamamoto, Takenori Ozaki, Atsumi Nitta, Toshitaka Nabeshima, Yoshiki Morita, Masashi Mizuno, Yasuhiko Ito, Yukio Yuzawa, Seiichi Matsuo

Research output: Contribution to journalArticle

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Abstract

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-β1 (TGF-β1), 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 α-smooth muscle actin (α-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-β1, 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number6
DOIs
Publication statusPublished - 01-12-2009
Externally publishedYes

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Peritoneal Fibrosis
Tissue Plasminogen Activator
Fibrinolysin
Matrix Metalloproteinase 16
Matrix Metalloproteinase 14
Tissue Inhibitor of Metalloproteinase-2
Matrix Metalloproteinase 3
Tissue Inhibitor of Metalloproteinase-1
Plasminogen Activators
Matrix Metalloproteinase 2
Transforming Growth Factors
Matrix Metalloproteinases
Smad3 Protein
Tissue Inhibitor of Metalloproteinase-3
Gelatinases
Messenger RNA
Collagen Type III
Peritoneum
Peritoneal Dialysis
Intraperitoneal Injections

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Kurata, Kei ; Maruyama, Shoichi ; Kato, Sawako ; Sato, Waichi ; Yamamoto, Jun Ichiro ; Ozaki, Takenori ; Nitta, Atsumi ; Nabeshima, Toshitaka ; Morita, Yoshiki ; Mizuno, Masashi ; Ito, Yasuhiko ; Yuzawa, Yukio ; Matsuo, Seiichi. / Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice. In: American Journal of Physiology - Renal Physiology. 2009 ; Vol. 297, No. 6.
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title = "Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice",
abstract = "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-β1 (TGF-β1), 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 α-smooth muscle actin (α-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-β1, 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.",
author = "Kei Kurata and Shoichi Maruyama and Sawako Kato and Waichi Sato and Yamamoto, {Jun Ichiro} and Takenori Ozaki and Atsumi Nitta and Toshitaka Nabeshima and Yoshiki Morita and Masashi Mizuno and Yasuhiko Ito and Yukio Yuzawa and Seiichi Matsuo",
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Kurata, K, Maruyama, S, Kato, S, Sato, W, Yamamoto, JI, Ozaki, T, Nitta, A, Nabeshima, T, Morita, Y, Mizuno, M, Ito, Y, Yuzawa, Y & Matsuo, S 2009, 'Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice', American Journal of Physiology - Renal Physiology, vol. 297, no. 6. https://doi.org/10.1152/ajprenal.90330.2008

Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice. / Kurata, Kei; Maruyama, Shoichi; Kato, Sawako; Sato, Waichi; Yamamoto, Jun Ichiro; Ozaki, Takenori; Nitta, Atsumi; Nabeshima, Toshitaka; Morita, Yoshiki; Mizuno, Masashi; Ito, Yasuhiko; Yuzawa, Yukio; Matsuo, Seiichi.

In: American Journal of Physiology - Renal Physiology, Vol. 297, No. 6, 01.12.2009.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice

AU - Kurata, Kei

AU - Maruyama, Shoichi

AU - Kato, Sawako

AU - Sato, Waichi

AU - Yamamoto, Jun Ichiro

AU - Ozaki, Takenori

AU - Nitta, Atsumi

AU - Nabeshima, Toshitaka

AU - Morita, Yoshiki

AU - Mizuno, Masashi

AU - Ito, Yasuhiko

AU - Yuzawa, Yukio

AU - Matsuo, Seiichi

PY - 2009/12/1

Y1 - 2009/12/1

N2 - 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-β1 (TGF-β1), 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 α-smooth muscle actin (α-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-β1, 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.

AB - 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-β1 (TGF-β1), 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 α-smooth muscle actin (α-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-β1, 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.

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