Lai K N, Leung J C K, Chan L Y Y, Li F F K, Tang S C W, Lam M F, Tse K C, Yip T P, Chan T M, Wieslander A, Vlassara H
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong.
Clin Exp Immunol. 2004 Dec;138(3):466-75. doi: 10.1111/j.1365-2249.2004.02629.x.
Autoclaving peritoneal dialysate fluid (PDF) degrades glucose into glucose degradation products (GDPs) that impair peritoneal mesothelial cell functions. While glycation processes leading to formation of advanced glycation end-products (AGE) were viewed commonly as being mediated by glucose present in the PDF, recent evidence indicates that certain GDPs are even more powerful inducers of AGE formation than glucose per se. In the present study, we examined the expression and modulation of AGE receptors on human peritoneal mesothelial cells (HPMC) cultured with GDPs, conventional PDF or PDF with low GDP content. HPMC cultured with GDPs differentially modulated AGE receptors (including RAGE, AGE-R1, AGE-R2 and AGE-R3) expression in a dose-dependent manner. At subtoxic concentrations, GDPs increased RAGE mRNA expression in HPMC. 2-furaldehyde (FurA), methylglyoxal (M-Glx) and 3,4-dideoxy-glucosone-3-Ene (3,4-DGE) increased the expression of AGE-R1 and RAGE, the receptors that are associated with toxic effects. These three GDPs up-regulated the AGE synthesis by cultured HPMC. In parallel, these GDPs also increased the expression of vascular endothelial growth factor (VEGF) in HPMC. PDF with lower GDP content exerted less cytotoxic effect than traditional heat-sterilized PDF. Both PDF preparations up-regulated the protein expression of RAGE and VEGF. However, the up-regulation of VEGF in HPMC following 24-h culture with conventional PDF was higher than values from HPMC cultured with PDF containing low GDP. We have demonstrated, for the first time, that in addition to RAGE, other AGE receptors including AGE-R1, AGE-R2 and AGE-R3 are expressed on HPMC. Different GDPs exert differential regulation on the expression of these receptors on HPMC. The interactions between GDPs and AGE receptors may bear biological relevance to the intraperitoneal homeostasis and membrane integrity.
对腹膜透析液（PDF）进行高压灭菌会将葡萄糖降解为葡萄糖降解产物（GDPs），这些产物会损害腹膜间皮细胞的功能。虽然导致晚期糖基化终产物（AGE）形成的糖基化过程通常被认为是由PDF中存在的葡萄糖介导的，但最近的证据表明，某些GDPs比葡萄糖本身更能诱导AGE的形成。在本研究中，我们检测了用GDPs、传统PDF或低GDP含量的PDF培养的人腹膜间皮细胞（HPMC）上AGE受体的表达和调节情况。用GDPs培养的HPMC以剂量依赖的方式差异性地调节AGE受体（包括RAGE、AGE-R1、AGE-R2和AGE-R3）的表达。在亚毒性浓度下，GDPs增加了HPMC中RAGE mRNA的表达。2-糠醛（FurA）、甲基乙二醛（M-Glx）和3,4-二脱氧葡萄糖-3-烯（3,4-DGE）增加了与毒性作用相关的受体AGE-R1和RAGE的表达。这三种GDPs上调了培养的HPMC中AGE的合成。同时，这些GDPs也增加了HPMC中血管内皮生长因子（VEGF）的表达。GDP含量较低的PDF比传统热灭菌的PDF具有更小的细胞毒性作用。两种PDF制剂均上调了RAGE和VEGF的蛋白表达。然而，用传统PDF培养24小时后，HPMC中VEGF的上调幅度高于用低GDP含量的PDF培养的HPMC。我们首次证明，除了RAGE外，其他AGE受体包括AGE-R1、AGE-R2和AGE-R3也在HPMC上表达。不同的GDPs对HPMC上这些受体的表达具有差异性调节作用。GDPs与AGE受体之间的相互作用可能与腹膜内稳态和膜完整性具有生物学相关性。
