Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis

Naoki Washida, Shu Wakino, Yukio Tonozuka, Koichiro Honma, Hirobumi Tokuyama, Yoshikazu Hara, Kazuhiro Hasegawa, Hitoshi Minakuchi, Keiko Fujimura, Kohji Hosoya, Koichi Hayashi, Hiroshi Itoh

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background. Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations.Methods. PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632.Results. Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-β, fibronectin and α-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-β expression and VEGF secretion, which were blocked by Y-27632.Conclusions. The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.

Original languageEnglish
Pages (from-to)2770-2779
Number of pages10
JournalNephrology Dialysis Transplantation
Volume26
Issue number9
DOIs
Publication statusPublished - 2011 Sep

Fingerprint

Peritoneal Fibrosis
rho-Associated Kinases
Chlorhexidine
Fibrosis
Transforming Growth Factors
Vascular Endothelial Growth Factor A
Glucose
Monomeric GTP-Binding Proteins
Angiogenesis Inducing Agents
Peritoneum
Peritoneal Dialysis
Fibronectins
Smooth Muscle Myocytes
Actins
Down-Regulation
Macrophages

Keywords

  • angiogenesis
  • peritoneal dialysis
  • peritoneal fibrosis
  • peritonium
  • Rho-kinase inhibitor

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis. / Washida, Naoki; Wakino, Shu; Tonozuka, Yukio; Honma, Koichiro; Tokuyama, Hirobumi; Hara, Yoshikazu; Hasegawa, Kazuhiro; Minakuchi, Hitoshi; Fujimura, Keiko; Hosoya, Kohji; Hayashi, Koichi; Itoh, Hiroshi.

In: Nephrology Dialysis Transplantation, Vol. 26, No. 9, 09.2011, p. 2770-2779.

Research output: Contribution to journalArticle

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abstract = "Background. Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations.Methods. PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632.Results. Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-β, fibronectin and α-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-β expression and VEGF secretion, which were blocked by Y-27632.Conclusions. The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.",
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author = "Naoki Washida and Shu Wakino and Yukio Tonozuka and Koichiro Honma and Hirobumi Tokuyama and Yoshikazu Hara and Kazuhiro Hasegawa and Hitoshi Minakuchi and Keiko Fujimura and Kohji Hosoya and Koichi Hayashi and Hiroshi Itoh",
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AU - Washida, Naoki

AU - Wakino, Shu

AU - Tonozuka, Yukio

AU - Honma, Koichiro

AU - Tokuyama, Hirobumi

AU - Hara, Yoshikazu

AU - Hasegawa, Kazuhiro

AU - Minakuchi, Hitoshi

AU - Fujimura, Keiko

AU - Hosoya, Kohji

AU - Hayashi, Koichi

AU - Itoh, Hiroshi

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N2 - Background. Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations.Methods. PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632.Results. Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-β, fibronectin and α-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-β expression and VEGF secretion, which were blocked by Y-27632.Conclusions. The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.

AB - Background. Peritoneal fibrosis (PF) and angiogenesis are typical morphological changes, leading to loss of peritoneal functions in patients undergoing peritoneal dialysis. The small G protein, Rho, and its downstream effector Rho-kinase have been shown to be involved in the tissue fibrosis process. This study was undertaken to investigate the role of Rho-kinase in the pathogenesis of these alterations.Methods. PF was induced by intraperitoneal administration of chlorhexidine (CHX) in male rats (CHX group). These rats were treated with a Rho-kinase inhibitor, fasudil (Fas group). Human pleural mesothelial cells, MeT-5A cells, were stimulated by glucose with or without another Rho-kinase inhibitor, Y-27632.Results. Peritoneal damage including peritoneal thickening, fibrous changes, macrophage migration and angiogenesis were evident in the CHX group and were ameliorated in the Fas group. The expression of markers of tissue fibrosis, such as transforming growth factor (TGF)-β, fibronectin and α-smooth muscle cell actin, were increased in the CHX group and were downregulated by fasudil. Similar results were also seen with an inducer of angiogenesis, vascular endothelial growth factor (VEGF). Rho-kinase was activated in the peritoneum of the CHX group, which was inhibited by fasudil. In MeT-5A cells, high glucose increased TGF-β expression and VEGF secretion, which were blocked by Y-27632.Conclusions. The activation of Rho-kinase is involved in peritoneal damage at multiple stages including tissue fibrosis and angiogenesis. The inhibition of Rho-kinase constitutes a novel strategy for the treatment of PF.

KW - angiogenesis

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