NDT Advance Access originally published online on June 2, 2007
Nephrology Dialysis Transplantation 2007 22(10):2838-2848; doi:10.1093/ndt/gfm323
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Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
Correspondence and offprint requests to: Dr Yasuhiko Tomino, Professor, Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. Email: yasu{at}med.juntendo.ac.jp
| Abstract |
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Background. The activity of gelatinase, matrix metalloproteinase-2, in effluent was increased in peritoneal dialysis patients with encapsulated peritoneal sclerosis (EPS) and in chlorhexidine gluconate-induced peritoneal sclerosing (PS) animal models. The objective of the present study was to investigate the effect of matrix metalloproteinase inhibitor (ONO-4817), an anticancer agent with anti-angiogenesis and anti-infiltration effects, on the development of peritoneal fibrosis in chlorhexidine gluconate-induced PS rats.
Methods. Forty-five Sprague–Dawley (S–D) rats were intraperitoneally injected with saline as control (n = 15) or with chlorhexidine gluconate (CH) (1.5 ml/100 g) in the CH group (n = 15). ONO-4817 (5 mg/rat) was administered intravenously to CH rats (the ONO-4817 group, n = 15) from initiation to the end of the study. After 22 days of ONO-4817 administration, the rats were sacrificed and the parietal peritoneum was harvested. The gene expressions of transforming growth factor-β (TGF-β),
-smooth muscle actin (
-SMA) and type I collagen in the peritoneum were analysed by the reverse transcription-polymerase chain reaction (RT–PCR). Peritoneal tissues were also evaluated immunohistologically.
Results. ONO-4817 significantly inhibited thickening of the submesothelial layer and accumulation of type I collagen in the peritoneum. ONO-4817 also prevented increases of the number of macrophages and blood vessels. The expressions of TGF-β,
-SMA and type I collagen in the peritoneum were markedly suppressed in ONO-4817-treated rats.
Conclusion. It appears that the administration of the MMP inhibitor ONO-4817 might be a new approach to the amelioration of PS.
Keywords: angiogenesis; cell infiltration; continuous ambulatory peritoneal dialysis (CAPD); matrix metalloproteinases (MMP); sclerosing peritonitis
Received for publication: 9. 4.06
Accepted in revised form: 2. 5.07
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