Treatment of established peritoneal fibrosis by gene transfer of Smad7 in a rat model of peritoneal dialysis.
OBJECTIVE
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.
Sun
Yanyan
Y
Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangdong, PR China.
Zhu
Fengxin
F
Yu
Xueqing
X
Nie
Jing
J
Huang
Fengxian
F
Li
Xiaoyan
X
Luo
Ning
N
Lan
Hui Yao
HY
Wang
Yongtao
Y
D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology* / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D018613:Microscopy, Confocal; D010530:Peritoneal Dialysis; D010537:Peritoneum; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051906:Smad7 Protein / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019076:Transgenes; D014465:Ultrasonics
D051906:Smad7 Protein; C497808:Smad7 protein, rat; D016212:Transforming Growth Factor beta