Advanced glycation end-products suppress neuropilin-1 expression in podocytes
Advanced glycation end-products suppress neuropilin-1 expression in podocytes
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DOI：
10.1038/ki.2008.603
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发表时间：
2009-03-01
影响因子：
19.6
通讯作者：
Wolf, Gunter
中科院分区：
文献类型：
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作者：
Bondeva, Tzvetanka;Ruester, Christiane;Wolf, Gunter
糖基化终末产物（AGEs）与糖尿病肾病的发病机制密切相关。在这里，我们测试了AGE修饰的牛血清白蛋白（AGE-BSA）对分化的小鼠足细胞培养的影响。差异显示和实时PCR分析表明，除了神经纤毛蛋白-1，整个信号受体复合物的神经纤毛蛋白-2，semaphorin-3A，和丛蛋白A1，显着减少AGE-BSA作为神经纤毛蛋白-1蛋白。与分离的系膜和肾小管上皮细胞相比，足细胞的作用是特异性的。此外，AGE-BSA对足细胞没有毒性。糖尿病db/db小鼠肾小球中Neutopilin-1的表达与其非糖尿病同窝小鼠相比降低。与移植供体相比，糖尿病肾病患者的肾活检中两种神经纤毛蛋白的转录物均减少。AGE-BSA抑制足细胞迁移，当siRNA下调neuropilin-1表达时，AGE-BSA不存在时发现类似的结果。与此相反，足细胞迁移刺激神经纤毛蛋白-1的过度表达，即使在AGE-BSA的存在下。我们的研究表明AGE-BSA通过下调neuropilin-1抑制足细胞迁移。迁移减少可能导致肾小球基底膜的未覆盖区域粘附到Bowman囊，从而导致局灶性肾小球硬化。
Advanced glycation end products (AGEs) have been linked to the pathogenesis of diabetic nephropathy. Here we tested the effect of AGE-modified bovine serum albumin (AGE-BSA) on differentiated mouse podocytes in culture. Differential display and real-time PCR analyses showed that in addition to neuropilin-1, the entire signaling receptor complex of neuropilin-2, semaphorin-3A, and plexin-A1, was significantly reduced by AGE-BSA as was neuropilin-1 protein. The effect was specific for podocytes compared to isolated mesangial and tubular epithelial cells. Further, AGE-BSA was not toxic to podocytes. Neutopilin-1 expression was decreased in glomeruli of diabetic db/db mice compared to their nondiabetic littermates. Transcripts of both neuropilins were found to be decreased in renal biopsies from patients with diabetic nephropathy compared to transplant donors. Podocyte migration was inhibited by AGE-BSA with similar results found in the absence of AGE-BSA when neuropilin-1 expression was down-regulated by siRNA. In contrast, podocyte migration was stimulated by overexpression of neuropilin-1 even in the presence of AGE-BSA. Our study shows that AGE-BSA inhibited podocyte migration by down-regulating neuropilin-1. The decreased migration could lead to adherence of uncovered areas of the glomerular basement membrane to Bowman's capsule contributing to focal glomerulosclerosis.