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Gene Transfer of Transforming Growth Factor-ß1 to the Rat Peritoneum: Effects on Membrane Function

PETER J. MARGETTS^*,, MARTIN KOLB, TOM GALT, CATHERINE M. HOFF, TY R. SHOCKLEY and JACK GAULDIE

^* Division of Nephrology, McMaster University, Hamilton, Canada
Centre for Gene Therapeutics, McMaster University, Hamilton, Canada
Renal Division Scientific Affairs, Baxter Healthcare Corp., McGaw Park, Illinois.

Correspondence to Dr. Jack Gauldie, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street W., Room 2N16, Hamilton, Ontario, Canada L8N 3Z5. Phone: 905-521-2100, ext. 76332; Fax: 905-577-0198; E-mail: gauldie{at}mcmaster.ca

Abstract. Long-term peritoneal dialysis is limited by physiologic changes in the peritoneum that lead to ultrafiltration failure. To determine the role of profibrotic cytokines in the alteration of peritoneal transport, a rodent model of transforming growth factor-ß (TGF-ß)-mediated peritoneal fibrosis was established. An adenoviral vector driving the active form of TGF-ß1 (AdTGFß1) was administered intraperitoneally, and peritoneal structure and function were evaluated for 28 d after infection. Seven days after AdTGFß1 infection, thickening of the peritoneum, with cellular proliferation and increased vascularization, was noted. By day 28, there was persistent thickening and extensive collagen deposition. The mesenteric collagen content was significantly elevated, compared with control adenovirus-treated animals, 21 d after infection (2.9 versus 1.8 mg hydroxyproline/g tissue, P = 0.006). Blood vessel density, as measured using factor VIII immunohistochemical analyses, was significantly increased from day 4 to day 21 but decreased by day 28. Animals infected with AdTGFß1 demonstrated increased transport of solutes and decreased net ultrafiltration, which was maximal on day 7 and returned to baseline levels by day 28. It was demonstrated in vitro and in vivo that TGF-ß1 induced production of vascular endothelial growth factor. Overexpression of TGF-ß1 after adenovirus-mediated gene transfer causes peritoneal fibrosis, neoangiogenesis, and increased peritoneal membrane solute transport. This model should allow further delineation of the relative contributions of profibrotic and angiogenic cytokines to changes in peritoneal function and may lead to potential new interventions for peritoneal membrane failure.

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