Antiangiogenic and antifibrotic gene therapy in a chronic infusion model of peritoneal dialysis in rats.
To identify the relative importance of peritoneal fibrosis and angiogenesis in peritoneal membrane dysfunction, adenoviral mediated gene transfer of angiostatin, a recognized angiogenesis inhibitor, and decorin, a transforming growth factor-beta-inhibiting proteoglycan, were used in a daily infusion model of peritoneal dialysis. A peritoneal catheter and subcutaneous port were inserted in rats. Five and fourteen d after insertion, adenovirus-expressing angiostatin, decorin, or AdDL70, a null control virus, were administered. Daily infusion of 4.25% Baxter Dianeal was initiated 7 d after catheter insertion and continued until day 35. Three initial doses of lipopolysaccharide were administered on days 8, 10, and 12 to promote an inflammatory response. Net ultrafiltration was used as a measure of membrane function, and peritoneum-associated vasculature and mesenteric collagen content was quantified. Ultrafiltration dysfunction, angiogenesis, and fibrosis were observed in daily infusion control animals. Animals treated with AdAngiostatin demonstrated an improvement in net ultrafiltration (-3.1 versus -7.8 ml for control animals; P = 0.0004) with a significant reduction in vessel density. AdDecorin-treated animals showed a reduction in mesenteric collagen content (1.8 versus 2.9 microg/mg; P = 0.04); however, AdDecorin treatment had no effect on net ultrafiltration. In a rodent model of peritoneal membrane failure, net ultrafiltration was significantly improved and peritoneal-associated blood vessels were significantly reduced by using adenovirus-mediated gene transfer of angiostatin. Decorin, a transforming growth factor-beta-inhibiting proteoglycan, reduced collagen content but did not affect net ultrafiltration. Improvement in the function of the peritoneum as a dialysis membrane after treatment with angiostatin has implications for treatment of peritoneal membrane dysfunction seen in patients on long-term dialysis.
Margetts
Peter J
PJ
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
Gyorffy
Steve
S
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
Kolb
Martin
M
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
Yu
Lisa
L
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
Hoff
Catherine M
CM
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
Holmes
Clifford J
CJ
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
Gauldie
Jack
J
*Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine and Division of Nephrology, McMaster University, Hamilton, Canada; and Baxter Healthcare Renal Division Scientific Affairs, Baxter Healthcare Corporation, McGaw Park, Illinois.
D043168:Angiostatins; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D058575:Decorin; D016326:Extracellular Matrix Proteins; D005355:Fibrosis / Q000517:prevention & control; D015316:Genetic Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010446:Peptide Fragments / Q000235:genetics* / Q000627:therapeutic use; D010530:Peritoneal Dialysis; D010537:Peritoneum / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D010958:Plasminogen / Q000235:genetics* / Q000627:therapeutic use; D011509:Proteoglycans / Q000235:genetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012449:Safety; D013997:Time Factors; D014652:Vascular Diseases / Q000188:drug therapy* / Q000473:pathology
D058575:Decorin; D016326:Extracellular Matrix Proteins; D010446:Peptide Fragments; D011509:Proteoglycans; D043168:Angiostatins; D010958:Plasminogen