Advanced glycation end products and the progressive course of renal disease
Advanced glycation end products and the progressive course of renal disease
复制标题
DOI：
10.1053/ajkd.2001.27414
复制
发表时间：
2001-10-01
影响因子：
13.2
通讯作者：
Schinzel, R
中科院分区：
文献类型：
--
作者：
Heidland, A;Sebekova, K;Schinzel, R
在实验性和人类糖尿病肾病（DN）中，已经表明晚期糖基化终产物（AGEs），特别是羧甲基赖氨酸和戊糖苷，与丙二醛一起在肾小球病变中积累，与疾病严重程度有关，并且在足细胞中存在上调的AGEs受体（AGEs）。AGEs的毒性作用是由血浆和细胞外基质（ECM）蛋白的结构和功能改变引起的，特别是蛋白质的交联以及AGEs与其受体和/或结合蛋白的相互作用。在肾小球系膜和内皮细胞中，AGE-β 2相互作用导致氧自由基的形成增强，随后核因子-κ B活化并释放促炎细胞因子（白细胞介素-6、肿瘤坏死因子-α）、生长因子（转化生长因子-β 1 [TGF-β 1]、胰岛素样生长因子-1）和粘附分子（血管细胞粘附分子-1、细胞间粘附分子-1）。在肾小管细胞中，与AGE白蛋白孵育后，刺激促分裂原活化蛋白（MAP）激酶通路及其下游靶点，活化蛋白-1（AP-1）复合物，TGF-β 1过表达，增强蛋白激酶C活性，降低细胞增殖，并损害蛋白降解速率，部分原因是组织蛋白酶活性降低。在正常血糖大鼠和小鼠中，通过胃肠外给予AGE白蛋白，导致肾小球TGF-β 1过度产生，ECM蛋白基因表达增强，形态学病变类似于DN，从而进一步证实了AGE的致病相关性。AGEs在DN中致病相关性的证据也来自实验研究，其中AGEs的形成和/或作用受到氨基胍、OPB-9195、吡哆胺、可溶性RAGE、丝氨酸蛋白酶胰蛋白酶和抗氧化剂的调节，从而改善细胞和/或肾功能。(C)2001年由国家肾脏基金会，公司。
In experimental and human diabetic nephropathy (DN), It has been shown that advanced glycation end products (AGEs), In particular, carboxymethyl-lysine and pentosidine, accumulate with malondialdehyde In glomerular lesions In relation to disease severity and in the presence of an upregulated receptor for AGE (RAGE) in podocytes. Toxic effects of AGEs result from structural and functional alterations in plasma and extracellular matrix (ECM) proteins, In particular, from cross-linking of proteins and interaction of AGEs with their receptors and/or binding proteins. In mesangial and endothelial cells, the AGE-RAGE interaction caused enhanced formation of oxygen radicals with subsequent activation of nuclear factor-kappaB and release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-alpha), growth factors (transforming growth factor-beta1 [TGF-beta1], insulin-like growth factor-1), and adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1). In tubular cells, incubation with AGE albumin was followed by stimulation of the mitogen-activating protein (MAP) kinase pathway and its downstream target, the activating protlen-1 (AP-1) complex, TGF-beta1 overexpression, enhanced protein kinase C activity, decreased cell proliferation, and Impaired protein degradation rate, in part caused by decreased cathepsin activities. The pathogenic relevance of AGEs was further verified by in vivo experiments in euglycemic rats and mice by the parenteral administration of AGE albumin, leading in the glomeruli to TGF-beta1 overproduction, enhanced gene expression of ECM proteins, and morphological lesions similar to those of DN. Evidence for the pathogenic relevance of AGEs in DN also comes from experimental studies in which the formation and/or action of AGEs was modulated by aminoguanidine, OPB-9195, pyridoxamine, soluble RAGEs, serine protease trypsin, and antioxidants, resulting in Improved cell and/or renal function. (C) 2001 by the National Kidney Foundation, Inc.