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: 5202002
• 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/5202002
• 关键词: RNase protection assay; albuminuria; aminoguanidine; collagen; crosslink; diabetic nephropathy; extracellular matrix; glomerulosclerosis; glucose metabolism; heparan sulfate; hyperglycemia; kidney cell; laboratory mouse; laboratory rat; laminin; 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 cross linking 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 `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-beta1 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。 事实上，胰岛素依赖型糖尿病和非胰岛素依赖型糖尿病的肾小球病变 相似的结果表明，葡萄糖代谢异常可能 参与他们的发展。 高血压导致 晚期糖基化终产物的积累。 这些产品 参与异常的，非代谢性的交联， 细胞基质成分。它们的积累可能有助于 糖尿病患者出现的硬化。 AGEs引发了大量的 由表面受体介导的生物反应， 在巨噬细胞、内皮细胞以及人和大鼠中进行了表征 系膜细胞使用正常小鼠系膜细胞，我们发现细胞 暴露于AGE的小鼠，使用 RNA酶保护测定：IV型胶原蛋白，蛋白聚糖硫酸乙酰肝素， 以及层粘连蛋白A和B链。 我们还发现， IV型胶原加入培养基中。 我们研究了注射 AGEs对完整动物的影响也是一样的。正常大鼠 长期注射AGE-白蛋白的患者出现蛋白尿， 出现局灶性肾小球硬化病变。 联合给药 氨基胍可抑制AGEs的交联， 病变我们还发现，正常小鼠的肾小球接受 重复注射AGEs显示出编码“1”的mRNA增加， IV型胶原和层粘连蛋白的B1链， 是体内肾小球对AGEs的反应。这些反应是相关的 TGF-β 1而不是PDGF信息水平增加。这些响应 当小鼠与氨基胍共处理时，没有发生。