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Perit Dial Int 29(5): 508-516
2009
© 2009 International Society for Peritoneal Dialysis
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Bench Sciences

PROLONGED PERITONEAL GENE EXPRESSION USING A HELPER-DEPENDENT ADENOVIRUS

Limin Liu1, Chang-Xin Shi2, Ayesha Ghayur1, Claire Zhang1, Je Yen Su1, Catherine M. Hoff3 and Peter J. Margetts1

Department of Medicine,1 McMaster University, Hamilton, Ontario, Canada; Division of Hematology and Oncology,2 Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona; Renal Division,3 Scientific Affairs, Baxter Healthcare, McGaw Park, Illinois, USA

Correspondence to: P.J. Margetts, Department of Medicine, McMaster University, Division of Nephrology, St. Joseph's Hospital, 50 Charlton Ave. E, Hamilton, Ontario L8N 4A6 Canada. margetts{at}mcmaster.ca

{diamondsuit} Background: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis. The causes of EPS are not well defined and are likely multifactorial. A suitable animal model would facilitate research into the pathophysiology and treatment of EPS.

{diamondsuit} Methods: We developed a helper-dependent adenovirus that expresses both green fluorescent protein (GFP) and active transforming growth factor-beta (TGF-β1; HDAdTGF-β1). Mice were administered HDAdTGF-β1 via intraperitoneal injection and the response was compared with mice administered either first-generation adenovirus expressing TGF-β1 (AdTGF-β1) or control adenovirus (AdGFP).

{diamondsuit} Results: HDAdTGF-β1-treated mice continued to express the GFP reporter transgene to day 74, the end of the observation period. Transgene expression lasted less than 28 days in the animals treated with first-generation adenoviruses. Animals treated with first-generation AdTGF-β1 demonstrated submesothelial thickening and angiogenesis at day 7, with almost complete resolution by day 28. The HDAdTGF-β1-treated mice demonstrated progressive peritoneal fibrosis with adhesion formation and encapsulation of bowels. Weight gain was significantly reduced in animals treated with HDAdTGF-β1 compared to both the control-treated animals and the AdTGF-β1-treated animals. Inflammation was not a major component of the fibroproliferative response.

{diamondsuit} Conclusions:Peritoneal administration of a first-generation AdTGF-β1 leads to transient gene expression, resulting in a resolving fibrotic response and histology similar to that seen in simple peritoneal sclerosis. Prolonged TGF-β1 expression induced by the helper-dependent HDAdTGF-β1 led to changes in peritoneal morphology resembling EPS. This suggests that TGF-β1 may be a contributing factor in both simple peritoneal sclerosis and EPS. This model will be useful for elucidation of the mechanism of EPS and evaluation of potential treatment.

KEY WORDS: Encapsulating peritoneal sclerosis; simple peritoneal sclerosis; first-generation adenovirus; helper-dependent adenovirus; transforming growth factor-beta (TGF-β1); gene therapy.

Received 16 August 2008; accepted 3 March 2009.




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