NDT Advance Access originally published online on July 9, 2008
Nephrology Dialysis Transplantation 2008 23(12):3831-3840; doi:10.1093/ndt/gfn369
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Preservation of peritoneal morphology and function by pentoxifylline in a rat model of peritoneal dialysis: molecular studies
1 Department of Internal Medicine, National Taiwan University Hospital 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
Correspondence and offprint requests to: Tun-Jun Tsai, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, Taiwan, Republic of China. Tel: +886-2-23123456 (ext. 9801058); Fax: +886-2-23934176; E-mail: tjtsai{at}ntuh.gov.tw
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Abstract |
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Background. High-glucose (HG) content of dialysate accelerated peritoneal fibrosis. We investigated in vitro mechanisms and the in vivo potential of pentoxifylline (PTX) to prevent this fibrogenic process.
Methods. For human peritoneal mesothelial cell (HPMC) culture, a normal-glucose (NG, 5.5 mM) or HG (138 mM) medium was established through pilot experiments. The rat peritoneal dialysis (PD) model consists of four groups (n = 8): group 1, intraperitoneal (IP) HG (4.25%) solution; group 2, as group 1 plus daily IP PTX (4 mg/in 1 h); group 3, IP PTX and group 4 as control.
Results. In HPMC culture, PTX significantly prevented HG-stimulated gene and protein production of collagen and transforming growth factor-β1 (TGF-ß1) (reduction rate of 72–81%). The p38 mitogen-activated protein kinase (MAPK) pathway was activated significantly in HG-treated HPMCs. Blockade of p38 MAPK by SB203580 (25 µM) or PTX (300 µg/ml) resulted in an effective suppression of collagen and TGF-ß1 gene expression in HG-cultured HPMCs. In PD experimental animals, peritoneal thickness and collagen expression in the peritoneum were significantly increased in HG-treated rats, and was attenuated by PTX (P < 0.01). Impaired peritoneal ultrafiltration (1.9 ± 0.5 ml versus 2.4 ± 0.4 ml, P < 0.05) and stimulated proinflammatory IL-6, MCP-1 and TGF-β1 activation were observed in HG-treated rats. PTX well preserved the functional characteristics of peritoneum and cytokine profiles.
Conclusions. These in vitro and in vivo data suggest that PTX may have therapeutic benefits for the prevention or retardation of peritoneal fibrosis.
Keywords: high glucose; mesothelial cell; pentoxifylline; TGF-β1; fibrosis
Received for publication: 17.11.07
Accepted in revised form: 9. 6.08