title: Peritoneal fibrosis and high transport are induced in mildly pre-injured peritoneum by 3,4-dideoxyglucosone-3-ene in mice.
abstract: Peritoneal dialysis (PD) solution contains high concentrations of glucose and glucose degradation products (GDPs). One of several GDPs--3,4-dideoxyglucosone-3-ene (3,4-DGE)--was recently identified as the most reactive and toxic GDP in PD fluids. In vitro, 3,4-DGE has been shown to induce mesothelial cell damage; however, its role in peritoneal fibrosis in vivo remains unclear. In the present study, we intraperitoneally administered chlorhexidine gluconate (CG) for mild peritoneal injury, and we then injected 3,4-DGE [38 μmol/L (low concentration) or 145 μmol/L (high concentration)] 5 times weekly for 4 weeks. Significant thickening of the parietal peritoneal membrane was observed only when treatment with low or high concentrations of 3,4-DGE occurred after CG administration, but not when either CG or 3,4-DGE alone was given. The combination of CG and 3,4-DGE also caused upregulation of messenger RNA expression of transforming growth factor β1, connective tissue growth factor, fibronectin, collagen type 1 α1 chain, alpha smooth muscle actin (α-SMA), vascular endothelial growth factor 164, NADPH oxidase 1 and 4, p22phox, p47phox, and gp91phox in peritoneal tissue. Treatment with CG alone was sufficient to cause significant F4/80-positive macrophage infiltration, appearance of α-SMA-positive cells, and vessel formation in the submesothelial layer. Addition of 3,4-DGE markedly enhanced those changes and induced apoptosis, mainly in leukocytes. The concentration of 3,4-DGE in the abdominal cavity declined more rapidly in CG-treated mice than in PBS-treated mice. Peritoneal membrane permeability determined by peritoneal equilibration test showed high transport conditions in peritoneum treated with both CG and 3,4-DGE. These results indicate that, when mild peritoneal damage is already present, 3,4-DGE causes peritoneal thickening and fibrosis, resulting in deterioration of peritoneal membrane function.
authors.affiliation: Department of Medicine and Clinical Science,Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
authors.forename: Masato
authors.initials: M
authors.lastname: Kasahara
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Takashige
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Naohiro
authors.initials: N
authors.lastname: Toda
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Shinji
authors.initials: S
authors.lastname: Namoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Nana
authors.initials: N
authors.lastname: Seki
authors.forename: Nozomi
authors.initials: N
authors.lastname: Souma
authors.forename: Taku
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002710:Chlorhexidine / Q000031:analogs & derivatives; D015314:Dialysis Solutions / Q000009:adverse effects*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010530:Peritoneal Dialysis / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011753:Pyrones / Q000009:adverse effects*
chemical_list: C504711:3,4-dideoxyglucosone-3-ene; D000199:Actins; D015314:Dialysis Solutions; D011753:Pyrones; C010882:chlorhexidine gluconate; D002710:Chlorhexidine