Methylglyoxal induces peritoneal thickening by mesenchymal-like mesothelial cells in rats.
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-beta (TGF-beta), 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-beta, 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.
Hirahara
Ichiro
I
Division of Total Renal Care Medicine, Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan. hirahara@rpf.jp
Ishibashi
Yoshitaka
Y
Kaname
Shinya
S
Kusano
Eiji
E
Fujita
Toshiro
T
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D015314:Dialysis Solutions / Q000633:toxicity; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005557:Formaldehyde / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011765:Pyruvaldehyde / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D024042:Collagen Type I; D017931:DNA Primers; D015314:Dialysis Solutions; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D005557:Formaldehyde; D011765:Pyruvaldehyde; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D005947:Glucose