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: 3776700
• 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/3776700
• 关键词: RNase protection assay; albumins; basement membrane; collagen; crosslink; diabetic nephropathy; extracellular matrix; fibronectins; genetic regulation; glomerulosclerosis; glucose metabolism; glycosylation; heparan sulfate; hyperglycemia; kidney cell; laboratory mouse; laboratory rat; laminin; macrophage; messenger RNA; nuclear runoff assay; platelet derived growth factor; proteoglycan; receptor binding; vascular endothelium

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.

终末期肾小球硬化是糖尿病的主要并发症 糖尿病。 事实上，在胰岛素依赖型糖尿病和非胰岛素依赖型糖尿病肾小球病变， 类似的结果表明，葡萄糖代谢异常可能参与 在他们的发展。 高血压导致高级 糖基化终产物。 这些产品参与异常，非- 细胞外基质成分的可代谢交联。他们的 积累可能导致糖尿病患者中观察到的硬化。 年龄 引发大量的生物反应， 已经在巨噬细胞、内皮细胞、 细胞以及人和大鼠系膜细胞。使用正常小鼠系膜 细胞，我们研究了AGE对基底膜合成的影响。 膜组件接种在AGE上的细胞显示出增加的 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。由于这些观察是在体外进行的，我们检查了 对完整动物施用AGEs是否会产生类似的 方面的影响.正常小鼠的肾小球接受重复注射 AGEs表现出编码α 1 IV型胶原蛋白的mRNAS增加， 对于层粘连蛋白的B1链，确定存在肾小球 对AGEs的反应。