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Diabetes. 2010 Aug;59(8):1915-25. doi: 10.2337/db09-0663. Epub 2010 Jun 3.

Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy.

Author information

1
Department of Nephrology, Chang Gung Memorial Hospital atChiayi, Chiayi, Taiwan. linchunliang@adm.cgmh.org.tw

Abstract

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.

PMID:
20522599
PMCID:
PMC2911050
DOI:
10.2337/db09-0663
[Indexed for MEDLINE]
Free PMC Article
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