Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy.
Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy.
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作者：
Lin CL;Wang FS;Hsu YC;Chen CN;Tseng MJ;Saleem MA;Chang PJ;Wang JY
足细胞紊乱通常与明显的蛋白尿有关，这是糖尿病肾病的一个标志。本研究旨在研究Notch-1信号在高糖应激人足细胞和糖尿病动物模型中的调节作用。通过RT-qPCR、Western印迹分析和免疫组织化学染色，检测HG处理的足细胞、人胚胎肾细胞(HEK293)和糖尿病动物肾脏中Notch信号成分的表达。评估Notch信号、血管内皮生长因子表达和足细胞完整性之间的关系。在HG培养的人足细胞和糖尿病动物的HEK293细胞和肾脏中，Noch-1信号显著激活。HG还增加了血管内皮生长因子的表达，减少了newitin的表达和足细胞的数量--这是糖尿病肾病蛋白尿发生的关键事件。在使用药物调节剂或特定的shRNA敲除策略后，抑制Notch-1信号显著地抑制了HG应激细胞中的VEGF激活和neparin抑制，并改善了糖尿病肾脏的蛋白尿。我们的研究结果表明，在HG处理的肾小管足细胞中，Notch-1信号的上调诱导了血管内皮生长因子的表达，以及随后的内弗林抑制和细胞凋亡。Notch-1信号的调节有望成为治疗糖尿病肾病的新的治疗策略。
Disturbances in podocytes are typically associated with marked proteinuria, a hallmark of diabetic nephropathy. This study was conducted to investigate modulation of Notch-1 signaling in high glucose (HG)-stressed human podocytes and in a diabetic animal model. Expression of the Notch signaling components was examined in HG-treated podocytes, human embryonic kidney cells (HEK293), and kidneys from diabetic animals by RT-qPCR, Western blot analysis, and immunohistochemical staining. The association between the Notch signaling, VEGF expression, and podocyte integrity was evaluated. Notch-1 signaling was significantly activated in HG-cultured human podocytes and HEK293 cells and kidneys from diabetic animals. HG also augmented VEGF expression, decreasing nephrin expression and podocyte number—a critical event for the development of proteinuria in diabetic nephropathy. After use of pharmacological modulators or specific shRNA knockdown strategies, inhibition of Notch-1 signaling significantly abrogated VEGF activation and nephrin repression in HG-stressed cells and ameliorated proteinuria in the diabetic kidney. Our findings suggest that upregulation of Notch-1 signaling in HG-treated renal podocytes induces VEGF expression and subsequent nephrin repression and apoptosis. Modulation of Notch-1 signaling may hold promise as a novel therapeutic strategy for the treatment of diabetic nephropathy.
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