De Vriese An S, Flyvbjerg Allan, Mortier Siska, Tilton Ronald G, Lameire Norbert H
*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
J Am Soc Nephrol. 2003 Aug;14(8):2109-2118. doi: 10.1681/ASN.V1482109.
The peritoneal membrane of long-term peritoneal dialysis patients is characterized by a loss of ultrafiltration capacity, associated morphologically with submesothelial fibrosis and neoangiogenesis. Exposure to high glucose concentrations in peritoneal dialysate and the resultant advanced glycation end-products (AGE) accumulation have been implicated in the development of these changes, but their exact pathophysiological role is unknown. We examined the effect of the interaction of AGE with one of their receptors (i.e., RAGE) on the function and structure of the peritoneum exposed to high ambient glucose concentrations. Streptozotocin-induced diabetic rats and control rats were treated during 6 wk with either neutralizing monoclonal anti-RAGE antibodies or control antibodies. The expression of RAGE was strongly enhanced in the peritoneal membrane of the diabetic animals. The diabetic peritonea were characterized by an elevated transport of small solutes, lower ultrafiltration rates, a higher vascular density, and an upregulation of endothelial nitric oxide synthase expression. These parameters were unaffected by treatment with anti-RAGE antibodies. In contrast, anti-RAGE but not control antibodies prevented upregulation of TGF-beta, development of submesothelial fibrosis, and fibronectin accumulation in the peritoneum of diabetic animals. In conclusion, binding of AGE to RAGE increases the expression of TGF-beta and contributes to the development of submesothelial fibrosis. Neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways.
长期腹膜透析患者的腹膜具有超滤能力丧失的特征，在形态学上与间皮下纤维化和新生血管形成相关。腹膜透析液中高葡萄糖浓度的暴露以及由此导致的晚期糖基化终产物（AGE）积累与这些变化的发生有关，但其确切的病理生理作用尚不清楚。我们研究了AGE与其一种受体（即RAGE）相互作用对暴露于高环境葡萄糖浓度下的腹膜功能和结构的影响。用中和性单克隆抗RAGE抗体或对照抗体对链脲佐菌素诱导的糖尿病大鼠和对照大鼠进行为期6周的治疗。糖尿病动物腹膜中RAGE的表达强烈增强。糖尿病腹膜表现为小溶质转运增加、超滤率降低、血管密度升高以及内皮型一氧化氮合酶表达上调。这些参数不受抗RAGE抗体治疗的影响。相反，抗RAGE抗体而非对照抗体可阻止糖尿病动物腹膜中TGF-β的上调、间皮下纤维化的发展以及纤连蛋白的积累。总之，AGE与RAGE的结合增加了TGF-β的表达，并促进了间皮下纤维化的发展。新生血管形成和由此导致的超滤能力丧失是由不同的致病途径介导的。
