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

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.

• Authors: Naoki Washida, Shu Wakino, Yukio Tonozuka, Koichiro Homma, Hirobumi Tokuyama, Yoshikazu Hara, Kazuhiro Hasegawa, Hitoshi Minakuchi, Keiko Fujimura, Kohji Hosoya, Koichi Hayashi, Hiroshi Itoh
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 26 Issue 9 Pg. 2770-9 (Sep 2011) ISSN: 1460-2385 [Electronic] England
• PMID: 21378147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Anti-Infective Agents, Local
• Enzyme Inhibitors
• Pyridines
• RNA, Messenger
• Transforming Growth Factor beta1
• Vascular Endothelial Growth Factor A
• Y 27632
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• rho-Associated Kinases
• fasudil
• Chlorhexidine

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, therapeutic use)
• Amides (therapeutic use)
• Animals
• Anti-Infective Agents, Local (pharmacology)
• Cells, Cultured
• Chlorhexidine (pharmacology)
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Epithelium (drug effects, metabolism)
• Humans
• Immunoenzyme Techniques
• Male
• Neovascularization, Pathologic (metabolism, pathology, prevention & control)
• Peritoneal Fibrosis (metabolism, pathology, prevention & control)
• Pleural Cavity (drug effects, metabolism)
• Pyridines (therapeutic use)
• RNA, Messenger (genetics)
• Rats
• Rats, Wistar
• Real-Time Polymerase Chain Reaction
• Transforming Growth Factor beta1 (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• rho-Associated Kinases (antagonists & inhibitors, genetics, metabolism)