Treatment of established peritoneal fibrosis by gene transfer of Smad7 in a rat model of peritoneal dialysis.

Abstract

BACKGROUND/AIMS:

It has been shown that blockade of TGF-beta1 signaling with Smad7 prevents experimental peritoneal fibrosis. The present study investigated whether Smad7 has a therapeutic effect on established peritoneal fibrosis associated with peritoneal dialysis (PD).

METHODS:

A rat model of peritoneal fibrosis was induced by a daily intraperitoneal infusion of 4.25% Dianeal. After peritoneal fibrosis had been established on day 14, groups of 6 rats were treated intraperitoneally with gene transfer of Smad7 or control plasmids using an ultrasound-microbubble-mediated system for 2 weeks until day 28. In addition, a group of 6 diseased rats was euthanized on day 14 before treatment as the basal disease control.

RESULTS:

Compared to the control-treatment animals on day 28, real-time PCR, Western blot, and confocal microscopy revealed that Smad7 gene transfer significantly attenuated the increased peritoneal fibrosis including the thickening of fibrotic peritoneum, accumulation of alpha-SMA and collagen I, and an improvement in peritoneal dysfunction (all p < 0.05). Importantly, Smad7 treatment also improved the severity of peritoneal fibrosis and functional impairment when compared to those on day 14 before treatment (all p < 0.05). Inhibition of the established peritoneal fibrosis by Smad7 was associated with an abrogation of TGF-beta signaling and upregulation of TGF-beta1 and PAI-1.

CONCLUSIONS:

Smad7 gene therapy is able to inhibit established peritoneal fibrosis in a rat model of PD. Results from this study suggest that Smad7 may be a therapeutic agent for the treatment of peritoneal fibrosis associated with PD.

• Authors: Yanyan Sun, Fengxin Zhu, Xueqing Yu, Jing Nie, Fengxian Huang, Xiaoyan Li, Ning Luo, Hui Yao Lan, Yongtao Wang
• Journal: American journal of nephrology (Am J Nephrol) Vol. 30 Issue 1 Pg. 84-94 ( 2009) ISSN: 1421-9670 [Electronic] Switzerland
• PMID: 19223683 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Smad7 Protein
• Smad7 protein, rat
• Transforming Growth Factor beta

Topics

• Animals
• Disease Models, Animal
• Fibrosis (pathology, therapy)
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Microscopy, Confocal
• Peritoneal Dialysis
• Peritoneum
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Smad7 Protein (genetics, physiology)
• Time Factors
• Transforming Growth Factor beta (metabolism)
• Transgenes
• Ultrasonics