GLOMERULAR EFFECTS OF ADVANCED GLYCOSYLATION END PRODUCTS

高级糖基化最终产物对肾小球的影响

• 批准号: 3754540
• 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/3754540
• 关键词: RNase protection assay; albuminuria; aminoguanidine; collagen; crosslink; diabetic nephropathy; extracellular matrix; glomerulosclerosis; glucose metabolism; glycosylation; heparan sulfate; hyperglycemia; kidney cell; laboratory mouse; laboratory rat; laminin; messenger RNA; pathologic process; platelet derived growth factor; renal glomerulus; transforming growth factors

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 showed that cells exposed to AGE had 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. We explored the effects of injections of AGEs to the intact animal would have similar effects. normal rats receiving long-term injections of AGE-Albumin had albuminuria and developed focal sclerotic glomerular lesions. The coadministration of aminoguanidine which inhibits crosslinking of AGEs prevented the renal lesions. We also found that the glomeruli of normal mice receiving repeated injections of AGEs exhibited an increase in mRNAs coding for alpha-1 type IV collagen and for the B1 chain of laminin establishing that there is a glomerular response to AGEs in vivo. These responses were associated with an increase in TGF-beta-1 but not PDGF message level. These responses did not occur when the mice were cotreated with aminoguanidine.

终末期肾小球硬化是糖尿病的主要并发症 糖尿病。IDDM和NIDDM患者的肾小球病变 表明葡萄糖代谢的异常可能 参与他们的发展。高血糖会导致 晚期糖基化终末产物的积累。这些产品 参与异常的、非代谢的交联体-- 细胞基质成分。它们的积累可能有助于 糖尿病患者中观察到的硬化症。年龄会引发大量的 由表面受体介导的生物反应 已在巨噬细胞、内皮细胞、人和大鼠身上表现出特征 系膜细胞。使用正常的小鼠系膜细胞，我们发现细胞 随着年龄的增长，下列mRNA水平增加 核糖核酸酶保护试验：IV型胶原、蛋白多糖、硫酸乙酰肝素、 以及层粘连蛋白A和B链。我们还发现，增加了对 将IV型胶原蛋白放入培养液中。我们研究了注射的效果。 对于完好的动物来说，年龄的变化也会有类似的效果。正常大鼠 接受长期注射AGE-白蛋白的患者出现蛋白尿和 出现局灶性硬化性肾小球病变。共同管理 抑制糖基化终末糖基化终末产物交联的氨基胍可预防肾脏 损伤。我们还发现，正常小鼠的肾小球 重复注射AGEs显示编码的mRNAs增加 α-1IV型胶原和层粘连蛋白B1链的建立 体内存在对AGEs的肾小球反应。这些回应是 与转化生长因子-β-1水平升高有关，但与PDGF消息水平无关。 当小鼠被联合处理时，这些反应不会发生 氨基胍。