期刊
DIABETES
卷 59, 期 8, 页码 1915-1925出版社
AMER DIABETES ASSOC
DOI: 10.2337/db09-0663
关键词
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资金
- National Science Council of Taiwan [NMRPG180661]
- Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan [CMRPG680351]
OBJECTIVE-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 RESEARCH DESIGN AND METHODS-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. RESULTS-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. CONCLUSIONS-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 Diabetes 59:1915-1925, 2010
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