De Vriese An S
Renal Unit, University Hospital Gent, Belgium.
Perit Dial Int. 2005 Jan-Feb;25(1):8-11.
Several conditions in the peritoneal membrane of peritoneal dialysis (PD) patients promote the accumulation of advanced glycation end-products (AGEs), that is, the uremic state, exposure to high glucose concentrations, and exposure to glucose degradation products (GDPs). AGEs exert some of their biologic actions through binding with a cell surface receptor, termed RAGE. Interaction of AGEs with RAGE induces sustained cellular activation, including the production of the fibrogenic growth factor, transforming growth factor-beta (TGF-beta). TGF-beta is pivotal in the process of epithelial-to-mesenchymal transition, through which cells of epithelial origin acquire myofibroblastic characteristics. Myofibroblasts are involved in virtually all conditions of pathological fibrosis. Submesothelial fibrosis is an important feature in peritoneal biopsies of PD patients, especially of those with clinical problems. We therefore examined the role of RAGE in peritoneal fibrosis, in an animal model of uremia, of high glucose exposure, and of peritoneal dialysate exposure. All three models were characterized by accumulation of AGEs, upregulation of RAGE, and fibrosis. Antagonism of RAGE prevented the upregulation of TGF-beta and fibrosis in the peritoneal membrane. We further examined the underlying mechanism of peritoneal fibrosis in the uremic model. Prominent myofibroblast transdifferentiation of mesothelial cells was identified by co-localization of cytokeratin and alpha-smooth muscle actin in submesothelial and interstitial fibrotic tissue. Antagonism of RAGE prevented conversion of mesothelial cells to myofibroblasts in uremia. In conclusion, we hypothesize that accumulation of AGEs in the peritoneal membrane, as a consequence of the uremic environment, chronic exposure to high glucose, and exposure to GDPs, results in an increased expression of RAGE. The interaction of AGEs with RAGE induces peritoneal fibrosis by virtue of upregulation of TGF-beta and subsequent conversion of mesothelial cells into myofibroblasts.
腹膜透析（PD）患者腹膜的几种情况会促进晚期糖基化终产物（AGEs）的积累，即尿毒症状态、暴露于高糖浓度以及暴露于葡萄糖降解产物（GDPs）。AGEs通过与一种称为RAGE的细胞表面受体结合发挥其一些生物学作用。AGEs与RAGE的相互作用诱导持续的细胞活化，包括促纤维化生长因子转化生长因子-β（TGF-β）的产生。TGF-β在上皮-间质转化过程中起关键作用，通过该过程上皮来源的细胞获得肌成纤维细胞特征。肌成纤维细胞几乎参与所有病理性纤维化情况。间皮下纤维化是PD患者腹膜活检的一个重要特征，尤其是那些有临床问题的患者。因此，我们在尿毒症、高糖暴露和腹膜透析液暴露的动物模型中研究了RAGE在腹膜纤维化中的作用。所有这三种模型的特征都是AGEs积累、RAGE上调和纤维化。RAGE拮抗可防止腹膜中TGF-β上调和纤维化。我们进一步研究了尿毒症模型中腹膜纤维化的潜在机制。通过细胞角蛋白和α-平滑肌肌动蛋白在间皮下和间质纤维化组织中的共定位，确定了间皮细胞明显的肌成纤维细胞转分化。RAGE拮抗可防止尿毒症中间皮细胞转化为肌成纤维细胞。总之，我们假设由于尿毒症环境、长期暴露于高糖和暴露于GDPs，腹膜中AGEs的积累导致RAGE表达增加。AGEs与RAGE的相互作用通过上调TGF-β并随后将间皮细胞转化为肌成纤维细胞而诱导腹膜纤维化。
