NDT Advance Access originally published online on February 19, 2004
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Nephrol Dial Transplant (2004) 19: 1293-1297
Nephrol Dial Transplant Vol. 19 No. 5 © ERA-EDTA 2004; all rights reserved
Technical Note
Recombinant adenovirus administration in rat peritoneum: endothelial expression and safety concerns
1Department of Biochemistry and Nutrition, Medical School, Université Libre de Bruxelles and 2Division of Nephrology, Université catholique de Louvain, Brussels, Belgium
Correspondence and offprint requests to: C. Delporte, Department of Biochemistry and Nutrition CP 611, Blg G/E, Medical School, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium. Email: cdelport{at}ulb.ac.be
Abstract
Background. Initial studies of adenovirus-mediated gene transfer to the peritoneum have shown transgene expression in the mesothelium from the parietal peritoneum. Using a replication-deficient adenovirus encoding ß-galactosidase (AdßGal), we investigated the expression efficiency and the distribution of the transgene to different areas of both visceral and parietal peritoneum and to extra-peritoneal tissues.
Methods. Male Wistar rats received an intraperitoneal injection of 15 ml of 0.9% NaCl alone or containing 1 x 109 or 3 x 109 p.f.u. of AdßGal. Evaluations of the histology of the peritoneum, the transgene expression and the safety of adenovirus-mediated gene transfer, using measurement of both ßGal activity and staining, were performed 1, 3 and 5 days post-injection.
Results. At 1 day post-injection of x 109 p.f.u. of AdßGal, significant ßGal activity and staining were detected in the omentum and mesenteric peritoneum. ßGal staining was observed in endothelial cells, mesothelial cells and adipocytes. Focal mononuclear infiltrates restricted to the submesothelial area of the visceral peritoneum were also observed. No expression was detected in the mesocolon and parietal peritoneum, where the mesothelium was damaged. Significant ßGal activity and staining were observed in lymph nodes, lungs, liver, heart and kidneys, in the absence of inflammatory changes.
Conclusions. Intraperitoneal delivery of adenoviral vectors allows highly efficient transgene expression in mesothelial cells, but also in endothelial cells and adipocytes of the visceral peritoneum. Adverse focal mononuclear infiltrates, as well as spreading of the adenoviral vector from the abdominal cavity to the systemic circulation, were observed in parallel. Transgene expression in endothelial cells is potentially important since the latter play a key role in the alterations of the peritoneal membrane associated with long-term peritoneal dialysis. However, these data emphasize the need for less immunogenic adenoviral vectors, ideally containing an endothelial cell-specific promoter, to overcome immune response-related problems and spreading to extra-peritoneal tissues.
Keywords: adenovirus; endothelium; gene transfer; mesothelium; peritoneum
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