Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats.
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-beta (TGF-beta), alpha-smooth muscle actin (alpha-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-beta, alpha-SMA and type I collagen in the peritoneum were markedly suppressed in ONO-4817-treated rats.


CONCLUSIONS
It appears that the administration of the MMP inhibitor ONO-4817 might be a new approach to the amelioration of PS.
Ro
Yuuki
Y
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. yasu@med.juntendo.ac.jp
Hamada
Chieko
C
Inaba
Masanori
M
Io
Hiroaki
H
Kaneko
Kayo
K
Tomino
Yasuhiko
Y
D000199:Actins / Q000378:metabolism; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D002710:Chlorhexidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008264:Macrophages / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008954:Models, Biological; D010530:Peritoneal Dialysis; D010537:Peritoneum / Q000187:drug effects / Q000473:pathology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012598:Sclerosis / Q000188:drug therapy / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000199:Actins; D000890:Anti-Infective Agents; D024042:Collagen Type I; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D016212:Transforming Growth Factor beta; C010882:chlorhexidine gluconate; D002710:Chlorhexidine