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Perit Dial Int 27(5): 580-588 2007
© 2007 International Society for Peritoneal Dialysis
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Bench Sciences

EFFECTS OF SMAD7 OVEREXPRESSION ON PERITONEAL INFLAMMATION IN A RAT PERITONEAL DIALYSIS MODEL

Jing Nie1, Wenke Hao1, Xianrui Dou1, Xin Wang1, Ning Luo1, Hui Y. Lan2 and Xueqing Yu1

Department of Nephrology,1 First Affiliated Hospital, Sun Yat-sen University, Guangzhou; Department of Medicine,2 Center for Inflammatory Diseases and Molecular Therapies, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China

Correspondence to: X. Yu, Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080 People's Republic of China. yuxq{at}mail.sysu.edu.cn

{diamondsuit} Objective: Transforming growth factor-beta (TGF-ß) has been shown to play a role in peritoneal complications due to long-term peritoneal dialysis (PD). In this study, we examined the effects of the TGF-ß signaling pathway on peritoneal inflammation associated with PD in rats by over-expressing Smad7, an inhibitor of TGF-ß/Smad signaling.

{diamondsuit} Methods: Peritoneal inflammation was induced in male Sprague–Dawley rats by intraperitoneal injections of 4.25% glucose dialysate (100 mg/kg body weight) daily for 4 weeks, with the addition of lipopolysaccharides (0.6 mg/kg body weight) on days 8, 10, 12, 22, 24, and 26. Peritoneal Smad7 gene transfer was achieved using an ultrasound microbubble mediated, doxycycline regulated, Smad7-expressing plasmid on day 0 and day 14 after initiation of PD. An empty vector was used as control. All rats were sacrificed after 4 weeks of PD. Peritoneal inflammatory response, including infiltration of total leukocytes (OX-1 positive) and macrophages (ED-1 positive) and expression of interleukin (IL)-1ß and tumor necrosis factor-alpha (TNF-{alpha}), was examined by immunofluorescence and RT-PCR.

{diamondsuit} Results: After PD, peritoneal inflammation developed in control animals, as demonstrated by an increase in the number of OX-1-positive and ED-1-positive cells and upregulation of IL-1ß and TNF-{alpha} mRNA and protein expression. In contrast, in animals treated with Smad7 gene transfer, IL-1ß and TNF-{alpha} expression and OX-1-positive and ED-1-positive cell infiltration were significantly inhibited. Furthermore, prevention of peritoneal inflammation by overexpression of Smad7 was associated with inhibition of phosphorylation of Smad2/3, a downstream of the TGF-ß signaling pathway, as well as TGF-ß1 expression.

{diamondsuit} Conclusion: Overexpression of Smad7 suppresses peritoneal inflammation induced by high glucose and lipopolysaccharides. The ability of Smad7 gene transfer to inhibit peritoneal inflammation indicates that targeting TGF-ß/Smad signaling may represent a new therapeutic strategy for the treatment of peritoneal complications associated with PD.

KEY WORDS: Gene transfer; inflammatory cells; proinflammatory cytokines; Smad7; TGF-ß.

Received 10 August 2006; accepted 18 May 2007.






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