Bondeva Tzvetanka, Rüster Christiane, Franke Sybille, Hammerschmid Elke, Klagsbrun Michael, Cohen Clemens D, Wolf Gunter
Klinik für Innere Medizin III, Friedrich-Schiller-University, Jena, Germany.
Kidney Int. 2009 Mar;75(6):605-16. doi: 10.1038/ki.2008.603. Epub 2008 Nov 26.
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. Neuropilin-1 expression was decreased in glomeruli of diabetic db/db mice compared to their non-diabetic 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.
晚期糖基化终末产物（AGEs）与糖尿病肾病的发病机制有关。在此，我们检测了AGE修饰的牛血清白蛋白（AGE-BSA）对培养的分化小鼠足细胞的影响。差异显示和实时PCR分析表明，除了神经纤毛蛋白-1外，神经纤毛蛋白-2、信号素-3A和丛状蛋白-A1的整个信号受体复合物以及神经纤毛蛋白-1蛋白均被AGE-BSA显著降低。与分离的系膜细胞和肾小管上皮细胞相比，该作用对足细胞具有特异性。此外，AGE-BSA对足细胞无毒。与非糖尿病同窝小鼠相比，糖尿病db/db小鼠肾小球中的神经纤毛蛋白-1表达降低。与移植供体相比，糖尿病肾病患者肾活检组织中两种神经纤毛蛋白的转录本均减少。AGE-BSA抑制足细胞迁移，当通过小干扰RNA下调神经纤毛蛋白-1表达时，在无AGE-BSA的情况下也发现了类似结果。相反，即使在存在AGE-BSA的情况下神经纤毛蛋白-1的过表达也会刺激足细胞迁移。我们的研究表明，AGE-BSA通过下调神经纤毛蛋白-1抑制足细胞迁移。迁移减少可能导致肾小球基底膜未覆盖区域与鲍曼囊粘连，从而导致局灶性肾小球硬化。
