Gene transfer of transforming growth factor-beta1 to the rat peritoneum: effects on membrane function.
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-beta (TGF-beta)-mediated peritoneal fibrosis was established. An adenoviral vector driving the active form of TGF-beta1 (AdTGFbeta1) was administered intraperitoneally, and peritoneal structure and function were evaluated for 28 d after infection. Seven days after AdTGFbeta1 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 AdTGFbeta1 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-beta1 induced production of vascular endothelial growth factor. Overexpression of TGF-beta1 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.
Margetts
Peter J
PJ
Division of Nephrology, McMaster University, Hamilton, Canada.|Centre for Gene Therapeutics, McMaster University, Hamilton, Canada.
Kolb
Martin
M
Centre for Gene Therapeutics, McMaster University, Hamilton, Canada.
Galt
Tom
T
Centre for Gene Therapeutics, McMaster University, Hamilton, Canada.
Hoff
Catherine M
CM
Renal Division Scientific Affairs, Baxter Healthcare Corp., McGaw Park, Illinois.
Shockley
Ty R
TR
Renal Division Scientific Affairs, Baxter Healthcare Corp., McGaw Park, Illinois.
Gauldie
Jack
J
Centre for Gene Therapeutics, McMaster University, Hamilton, Canada.
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005355:Fibrosis; D018014:Gene Transfer Techniques; D008222:Lymphokines / Q000502:physiology; D008566:Membranes / Q000502:physiology; D010537:Peritoneum / Q000187:drug effects / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003094:Collagen