Modulation of Notch-1 Signaling Alleviates Vascular Endothelial Growth Factor–Mediated Diabetic Nephropathy
| Autor: | Pey-Jium Chang, Min-Jen Tseng, Chun-Liang Lin, Feng-Sheng Wang, Jeng-Yi Wang, Cheng-Nan Chen, Yen-Chen Hsu, Moin A. Saleem |
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| Rok vydání: | 2010 |
| Předmět: |
Vascular Endothelial Growth Factor A
medicine.medical_specialty Endocrinology Diabetes and Metabolism Notch signaling pathway Kidney Cell Line Podocyte Nephrin Diabetic nephropathy chemistry.chemical_compound Internal medicine Internal Medicine medicine Animals Humans Diabetic Nephropathies Receptor Notch1 Notch 1 DNA Primers biology urogenital system Podocytes Reverse Transcriptase Polymerase Chain Reaction medicine.disease Rats Vascular endothelial growth factor Vascular endothelial growth factor A Glucose Endocrinology medicine.anatomical_structure chemistry biology.protein RNA RNA Interference Amyloid Precursor Protein Secretases Signal transduction Signal Transduction Plasmids |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db09-0663 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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