NDT Advance Access published online on September 12, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn495
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Methylglyoxal induces peritoneal thickening by mesenchymal-like mesothelial cells in rats
1 Division of Total Renal Care Medicine, Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo 2 Division of Nephrology, Department of Medicine, Jichi Medical School, Tochigi 3 1st Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan
Correspondence and offprint requests to: Ichiro Hirahara, Division of Total Renal Care Medicine, Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan. Tel: +81-3-5800-9176; Fax: +81-3-5800-9175; E-mail: hirahara{at}rpf.jp
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Abstract |
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Background. The epithelial-to-mesenchymal transition (EMT) of mesothelial cells was observed in patients on peritoneal dialysis and may be involved in peritoneal thickening. Conventional peritoneal dialysis fluids (PDFs) that contain glucose degradation products (GDPs), such as methylglyoxal (MGO) and formaldehyde (FA), are bioincompatible. The aim of this study is to analyse the participation of EMT in peritoneal thickening induced by GDPs in rats.
Methods. Rat mesothelial cells were cultured with various GDPs, and the gene expression of Snail was analysed by polymerase chain reaction (PCR). Sprague-Dawley rats were administered intraperitoneally 20 mM MGO/PDFs, 20 mM FA/PDFs or 0.1% chlorhexidine gluconate (CHX)/15% ethanol/saline every day for 21 days. On Day 22, the expression of transforming growth factor-β (TGF-β), collagen 1, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF), Snail and receptor for advanced glycation end-products (RAGE) was analysed by PCR, enzyme-linked immunoassay or immunohistological staining.
Results. In cell-culture experiments, the expression of Snail was enhanced by MGO, but not FA. In rats treated with 20 mM MGO, peritoneal fibrous thickening with the proliferation of mesenchymal-like mesothelial cells was observed. The expression of TGF-β, collagen 1, MMP-2, VEGF, Snail and RAGE increased significantly (P < 0.01). In FA- or CHX-treated rats, the peritoneum was thickened with sparse collagen fibres, but mesenchymal-like mesothelial cells were not observed.
Conclusions. MGO induced peritoneal fibrous thickening with the proliferation of mesenchymal-like mesothelial cells in vivo. These cells may be transdifferentiated from mesothelial cells by EMT via Snail and play an important role in peritoneal fibrous thickening.
Keywords: epithelial-to-mesenchymal transition (EMT); methylglyoxal; matrix metalloproteinase-2 (MMP-2); peritoneal thickening; transforming growth factor-β (TGF-β)
Received for publication: 9. 4.07
Accepted in revised form: 8. 8.08