ADVANCED GLYCOSYLATION END PRODUCTS AND EFFECT OF MESANGIAL CELLS

高级糖基化最终产物和对系膜细胞的影响

• 批准号: 3840306
• 负责人: L J STRIKER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3840306
• 关键词: RNase protection assay; albumins; basement membrane; cell growth regulation; collagen; crosslink; diabetic nephropathy; extracellular matrix; fibronectins; genetic regulation; glomerulonephritis; glucose metabolism; glycosylation; heparan sulfate; hyperglycemia; kidney cell; laboratory mouse; laboratory rat; laminin; macrophage; messenger RNA; nephrosclerosis; nuclear runoff assay; proteoglycan; receptor binding; vascular endothelium

End-stage glomerulosclerosis constitutes a major complication of diabetes mellitus. The fact that the glomerular lesions of both type I and type II diabetes are similar suggests that abnormalities in glucose metabolism may participate in their development. Hyper-glycemia 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. Mesangial cells plated on various glycosylated extracellular matrix components produce an increased amount of fibronectin. 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. These observations provide further evidence that the accumulation of extracellular matrix components in diabetics is regulated at the gene level, and is correlated with an increase in mesangial cell turnover.

终末期肾小球硬化是糖尿病的主要并发症 糖尿病。 I型和II型肾小球病变 糖尿病是相似的，这表明葡萄糖代谢异常可能 参与他们的发展。 超声波导致 晚期糖基化终产物的积累。 这些产品 参与异常的、不可代谢的细胞外交联， 基质成分它们的积累可能会导致硬化 在糖尿病患者中观察到。 AGEs引发了大量的生物 由表面受体介导的反应， 在巨噬细胞、内皮细胞以及人和大鼠中表征 系膜细胞 系膜细胞接种于各种糖基化细胞外基质上 组分产生增加量的纤连蛋白。使用普通鼠标 在系膜细胞中，我们研究了AGE对系膜细胞合成 基底膜成分接种在AGE上的细胞显示出 使用RNA酶保护测定的下列mRNA：IV型胶原， 蛋白聚糖硫酸乙酰肝素和层粘连蛋白A和B链。 我们还发现 IV型胶原蛋白向培养基中的释放增加。 率 转录，通过核径流测定法测量，也刺激了 将细胞铺在糖基化牛血清白蛋白上。AGE受体抗体 抑制了mRNA的增加。PDGF抗体消除了 年龄反应。 这些观察提供了进一步的证据， 糖尿病患者细胞外基质成分的积累受到调节 在基因水平上，与肾小球系膜细胞的增加相关， 周转