Peritoneal Fibrosis and High Transport Are Induced in Mildly Pre-injured Peritoneum by 3,4-Dideoxyglucosone-3-ene in Mice
Peritoneal Fibrosis and High Transport Are Induced in Mildly Pre-injured Peritoneum by 3,4-Dideoxyglucosone-3-ene in Mice
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DOI：
10.3747/pdi.2011.00033
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发表时间：
2013-03
影响因子：
2.8
通讯作者：
H. Yokoi;M. Kasahara;K. Mori;T. Kuwabara;Naohiro Toda;R. Yamada;S. Namoto;Takashi Yamamoto;N. Seki;Nozomi Souma;Takuya Yamaguchi;A. Sugawara;M. Mukoyama;K. Nakao
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文献类型：
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作者：
H. Yokoi;M. Kasahara;K. Mori;T. Kuwabara;Naohiro Toda;R. Yamada;S. Namoto;Takashi Yamamoto;N. Seki;Nozomi Souma;Takuya Yamaguchi;A. Sugawara;M. Mukoyama;K. Nakao
腹膜透析 (PD) 溶液含有高浓度的葡萄糖和葡萄糖降解产物 (GDP)。几种 GDP 之一——3,4-二脱氧葡萄糖酮-3-烯 (3,4-DGE)——最近被确定为腹膜透析液中反应性最强、毒性最强的 GDP。在体外，3,4-DGE 已被证明可诱导间皮细胞损伤；然而，其在体内腹膜纤维化中的作用仍不清楚。在本研究中，我们腹腔注射葡萄糖酸氯己定（CG）以治疗轻度腹膜损伤，然后注射3,4-DGE[38 μmol/L（低浓度）或145 μmol/L（高浓度）]，每周5次，持续4周。仅当 CG 给药后用低浓度或高浓度 3,4-DGE 治疗时，才会观察到壁层腹膜显着增厚，但单独给予 CG 或 3,4-DGE 时则不会观察到。 CG和3,4-DGE的组合还导致腹膜中转化生长因子β1、结缔组织生长因子、纤连蛋白、1型胶原α1链、α平滑肌肌动蛋白(α-SMA)、血管内皮生长因子164、NADPH氧化酶1和4、p22phox、p47phox和gp91phox的信使RNA表达上调 组织。单独用 CG 治疗足以引起显着的 F4/80 阳性巨噬细胞浸润、α-SMA 阳性细胞出现以及间皮下层血管形成。添加 3,4-DGE 显着增强了这些变化并诱导细胞凋亡，主要是在白细胞中。 CG 处理的小鼠腹腔中 3,4-DGE 的浓度比 PBS 处理的小鼠下降得更快。通过腹膜平衡测试测定的腹膜渗透性显示，用 CG 和 3,4-DGE 处理的腹膜具有高转运条件。这些结果表明，当轻度腹膜损伤已经存在时，3,4-DGE会导致腹膜增厚和纤维化，导致腹膜功能恶化。
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.