ADVANCED GLYCOSYLATION END PRODUCTS AND EFFECT OF MESANGIAL CELLS

终末期肾小球硬化是糖尿病的主要并发症 糖尿病。IDDM和NIDDM的肾小球病变均为 类似的提示，葡萄糖代谢的异常可能参与了 在他们的发展过程中。高血糖导致晚期糖尿病的蓄积 糖基化最终产物。这些产品参与了非正常、非 细胞外基质成分的可代谢交联性。他们的 蓄积可能是糖尿病患者出现硬化症的原因之一。年龄 引发大量的生物反应，这些反应是由 巨噬细胞、内皮细胞上的表面受体 细胞、人和大鼠肾小球系膜细胞。使用正常小鼠系膜 细胞，我们研究了年龄对基底膜合成的影响。 膜组件。在AGE上培养的细胞显示出更多的 以下是使用核糖核酸酶保护试验的mRNAs：IV型胶原， 蛋白多糖、硫酸乙酰肝素、层粘连蛋白A和B链。我们还发现 IV型胶原蛋白释放到介质中的增加。这一速度 转录，通过核流失分析测量，也被刺激在 细胞接种在糖化牛血清白蛋白上。AGE受体抗体 抑制观察到的mRNAs的增加。抗血小板衍生生长因子的抗体使 年龄反应。自从这些观察是在体外进行的，我们已经检查了 对完好的动物进行年龄管理是否会有类似的 效果。反复给药的正常小鼠肾小球 AGEs显示编码甲型IV型胶原的mRNAs增加， 对于层粘连蛋白的Bl链，确定存在一个肾小球 体内对AGE的反应。

End-stage glomerulosclerosis constitutes a major complication of diabetes mellitus. The fact that the glomerular lesions in both IDDM and NIDDM are similar suggests that abnormalities in glucose metabolism may participate in their development. Hyperglycemia leads to the accumulation of advanced glycosylation end-products. These products participate in abnormal, non- metabolizable cross-linking of extra-cellular matrix components. Their accumulation may contribute to the sclerosis observed in diabetics. AGEs trigger a large number of biological reactions which are mediated by surface receptors that have been characterized on macrophages, endothelial cells, and human and rat mesangial cells. Using normal mouse mesangial cells, we investigated the effect of AGE on the synthesis of the basement membrane components. Cells plated on AGE showed increased levels of the following mRNAs using the RNAse protection assay: collagen type IV, proteoglycan heparan sulfate, and laminin A and B chains. We also found an increased release of collagen type IV into the medium. The rate of transcription, measured by nuclear run-off assays, was also stimulated in cells plated on glycosylated bovine serum albumin. AGE receptor antibodies inhibited the observed increase in mRNAs. Antibodies to PDGF abrogated the AGE response. Since these observations were made in vitro we have examined whether the administration of AGEs to the intact animal would have similar effects. The glomeruli of normal mice receiving repeated injections of AGEs exhibited an increase in mRNAS coding for alpha1 type IV collagen and for the Bl chain of laminin establishing that there is a glomerular response to AGEs in vivo.