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: 3855332
• 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/3855332
• 关键词: albumins; basement membrane; cell growth regulation; collagen; crosslink; diabetic nephropathy; extracellular matrix; fibronectins; genetic regulation; glomerulonephritis; glucose metabolism; glycosylation; heparan sulfate; 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 which participate in abnormal, non- metabolizable cross-linking of extra-cellular matrix components. Their accumulation may contribute to the sclerosis observed in diabetics, since AGEs trigger a large number of biological reactions through surface receptors that have been characterized on macrophages, endothelial cells, and human and rat mesangial cells. Mesangial cells plated on various components of glycosylated extracellular matrix produce an excess 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 mRNA levels of collagen type IV, proteoglycan heparan sulfate, and laminin A and B chains using the RNase protection assay. There was also an increased release of collagen type IV in the medium. The rate of transcription, measured by nuclear run-off assays, was also stimulated in cells plated on glycosylated bovine serum albumin. These observations provide further evidence that the accumulation of extra-cellular matrix components in diabetics is regulated at the gene level.

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。 过度兴奋导致 晚期糖基化终产物参与异常，非- 细胞外基质成分的可代谢交联。他们的 积累可能有助于糖尿病患者中观察到的硬化， AGEs通过细胞表面引发大量的生物反应， 已经在巨噬细胞，内皮细胞， 以及人和大鼠的系膜细胞。 系膜细胞接种于各种 糖基化的细胞外基质成分产生过量的 纤连蛋白。 使用正常小鼠系膜细胞，我们研究了 AGE对基底膜成分合成的影响。细胞 在AGE上平板显示IV型胶原mRNA水平增加， 蛋白聚糖硫酸乙酰肝素和层粘连蛋白A和B链 保护试验 IV型胶原蛋白的释放也增加 在介质中。 转录的速率，通过核流出来测量 在接种于糖基化牛血清上的细胞中， 白蛋白。 这些观察结果进一步证明， 糖尿病患者细胞外基质成分的表达是由基因调控的， 水平