Evidence linking glycated albumin to altered glomerular nephrin and VEGF expression, proteinuria, and diabetic nephropathy
Evidence linking glycated albumin to altered glomerular nephrin and VEGF expression, proteinuria, and diabetic nephropathy
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DOI：
10.1111/j.1523-1755.2005.00567.x
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发表时间：
2005-10-01
影响因子：
19.6
通讯作者：
Shearman, CW
中科院分区：
文献类型：
--
作者：
Cohen, MP;Chen, S;Shearman, CW
背景Amadori-葡萄糖加合物修饰的白蛋白通过其激活蛋白激酶C-β的能力与糖尿病肾病的发生有关，而不依赖于高血糖症（PKC-β），上调转化生长因子-β（TGF-β）系统，并刺激肾小球细胞中细胞外基质蛋白的表达，并且通过证明降低糖化白蛋白的负荷改善db/db小鼠中的肾结构和功能异常。探讨降低糖化白蛋白后的有益作用（包括减少白蛋白尿）是否与Amadori修饰蛋白对nephrin（对调节蛋白排泄至关重要的足细胞蛋白）和血管生成血管内皮生长因子（VEGF）（诱导微血管通透性）的影响有关，糖尿病db/db小鼠用抑制白蛋白非酶糖化的小分子处理。与非糖尿病db/m小鼠相比，糖尿病对照组表现出尿白蛋白和IV型胶原排泄增加，肾TGF-β 1蛋白水平升高，免疫印迹法检测肾小球nephrin免疫荧光和nephrin蛋白减少，肾小球VEGF免疫染色和肾VEGF蛋白含量增加。接受测试化合物的糖尿病动物显示蛋白尿显著降低、肾TGF-β 1蛋白正常化以及改变的肾小球nephrin和VEGF表达的显著恢复。这些发现因果地暗示了与糖尿病状态相关的糖化白蛋白增加，在糖尿病中发现的异常肾nephrin和VEGF表达中，从而促进蛋白尿和肾小球硬化。
Background. Albumin modified by Amadori-glucose adducts has been linked to the development of diabetic nephropathy through its ability, independent of hyperglycemia, to activate protein kinase C-beta (PKC-beta), up-regulate the transforming growth factor-beta (TGF-beta) system, and stimulate expression of extracellular matrix proteins in glomerular cells, and by the demonstration that reducing the burden of glycated albumin ameliorates renal structural and functional abnormalities in the db/db mouse.Methods. To probe whether the salutary effects consequent to lowering glycated albumin, which include reduction of albuminuria, relate to an influence of the Amadori-modified protein on nephrin, the podocyte protein critical to regulation of protein excretion, and on the angiogenic vascular endothelial growth factor (VEGF), which induces microvascular permeability, diabetic db/db mice were treated with a small molecule that inhibits the nonenzymatic glycation of albumin.Results. Compared to nondiabetic db/m mice, diabetic controls exhibited increased urinary excretion of albumin and type IV collagen, elevated renal TGF-beta 1 protein levels, reduced glomerular nephrin immunofluorescence and nephrin protein by immunoblotting, and increased glomerular VEGF immunostaining and renal VEGF protein content. Diabetic animals receiving test compound showed significant lowering of proteinuria, normalization of renal TGF-beta 1 protein, and significant restoration of altered glomerular nephrin and VEGF expression.Conclusion. The findings causally implicate the increased glycated albumin associated with the diabetic state in the abnormal renal nephrin and VEGF expression found in diabetes, thereby promoting proteinuria and glomerulosclerosis.