Schwenger Vedat, Morath Christian, Salava Alexander, Amann Kerstin, Seregin Yuri, Deppisch Reinhold, Ritz Eberhard, Bierhaus Angelika, Nawroth Peter P, Zeier Martin
Department of Medicine/Division of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany.
J Am Soc Nephrol. 2006 Jan;17(1):199-207. doi: 10.1681/ASN.2005020155. Epub 2005 Nov 30.
Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE-receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3+ T cells, increased NF-kappaB binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-beta1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3+ T cells and NF-kappaB binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-beta1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE-RAGE interaction.
腹膜透析受到腹膜形态学改变的限制。使用含有葡萄糖降解产物（GDP）的腹膜透析液（PDF）会在腹腔内产生晚期糖基化终产物（AGE）。目前尚不清楚腹膜损伤是否与AGE的AGE受体（RAGE）相互作用存在因果关系。在48只野生型（WT）小鼠和48只RAGE缺陷小鼠中，比较了不同GDP含量的PDF对腹膜形态学改变的影响。每天两次注入1 ml PDF，持续12周。每组8只动物，分别接受无处理（假手术）；假注入（假腹腔内注入）；或经过滤除菌、不含葡萄糖的传统低GDP或高GDP PDF处理。在体外（PDF中AGE荧光的产生）和体内（羧甲基赖氨酸的免疫组织化学），AGE形成出现了GDP依赖性增加。在接受高GDP处理的WT小鼠中，炎症和新生血管形成增强，伴随着CD3 + T细胞上调、NF-κB结合活性增加、凝集素增加以及血管内皮生长因子表达增加。此外，发现明显的间皮下纤维化，TGF-β1表达增加。与假腹腔内注入相比，WT小鼠暴露于低GDP仅导致轻度炎症和新生血管形成，且无纤维化。WT小鼠的结果与RAGE缺陷小鼠的结果形成对比，RAGE缺陷小鼠在长期暴露于含GDP的PDF后，未出现炎症（CD3 + T细胞和NF-κB结合活性）、新生血管形成（通过凝集素和血管内皮生长因子表达）或纤维化（TGF-β1表达）增加。PDF中GDP引起的腹膜损伤至少部分依赖于AGE-RAGE相互作用。
