Inhibition of Rho-kinase alleviates peritoneal fibrosis and angiogenesis in a rat model of peritoneal dialysis

Ren Fail. 2013 Aug;35(7):958-66. doi: 10.3109/0886022X.2013.808565.

Abstract

Background/aims: The present study investigated whether Rho-kinase inhibition had a therapeutic role on the pathogenesis of peritoneal fibrosis and angiogenesis.

Methods: A rat model of peritoneal dialysis was induced by a daily intraperitoneal infusion of 4.25% Dianeal. Those rats were treated with Rho-kinase inhibitor, fasudil. Immunofluorescence, Western blot and RT-PCR were used to detect the expression of TGF-β1, Collagen I, αSMA and VEGF in each group. Microvessel density (MVD) was measured by immunohistochemistry. Rho-kinase activity was determined by western immunoblotting.

Results: Rho-kinase was activated in the peritoneum of the PD group, which was inhibited by fasudil. Compared with PD group, the mRNA and protein expressions of TGF-β1, αSMA and Collagen I were significantly downregulated in fasudil treatment groups in a dose-dependent manner, and the expression of VEGF and peritoneal MVD was also significantly downregulated in fasudil treatment groups in a dose-dependent manner.

Conclusion: The Rho-kinase was activated in the peritoneum of the peritoneal dialysis rats, and the inhibition of Rho-kinase by fasudil can remarkably decrease peritoneal fibrosis and angiogenesis.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Actins / metabolism
  • Animals
  • Collagen Type I / metabolism
  • Dialysis Solutions / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Male
  • Microvessels / drug effects
  • Microvessels / pathology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / physiopathology
  • Peritoneal Dialysis / adverse effects*
  • Peritoneal Fibrosis / drug therapy*
  • Peritoneal Fibrosis / etiology
  • Peritoneal Fibrosis / metabolism
  • Peritoneal Fibrosis / physiopathology
  • Peritoneum / blood supply
  • Peritoneum / drug effects
  • Peritoneum / metabolism
  • Peritoneum / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta1 / metabolism
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / metabolism
  • rho-Associated Kinases* / antagonists & inhibitors
  • rho-Associated Kinases* / metabolism

Substances

  • Actins
  • Collagen Type I
  • Dialysis Solutions
  • Protein Kinase Inhibitors
  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor A
  • smooth muscle actin, rat
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • fasudil