Ranibizumab interacts with the VEGF-A/VEGFR-2 signaling pathway in human RPE cells at different levels |
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Affiliation: | 1. Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India;2. Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India;1. Medical Biochemistry and Molecular Biology, University of the Saarland, Building 44, D-66424 Homburg, Germany;2. Bioorganic Chemistry, University of the Saarland, P.O. Box 151150, D-66123 Saarbrücken, Germany |
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Abstract: | Vascular endothelial growth factor (VEGF) secreted by the retinal pigment epithelium (RPE) plays an important role in ocular homeostasis, but also in diseases, most notably age-related macular degeneration (AMD). To date, anti-VEGF drugs like ranibizumab have been shown to be most effective in treating these pathologic conditions. However, clinical trials suggest that the RPE could degenerate and perish through anti-VEGF treatment. Herein, we evaluated possible pathways and outcomes of the interaction between ranibizumab and human RPE cells (ARPE-19). Results indicate that ranibizumab affects the VEGF-A metabolism in RPE cells from an extra- as well as intracellular site. The drug is taken up into the cells, with the VEGF receptor 2 (VEGFR-2) being involved, and decreases VEGF-A protein levels within the cells as well as extracellularly. Oxidative stress plays a key role in various inflammatory disorders of the eye. Our results suggest that oxidative stress inhibits RPE cell proliferation. This anti-proliferative effect on RPE cells is significantly enhanced through ranibizumab, which does not inhibit RPE cell proliferation substantially in absence of relevant oxidative stress. Therefore, we emphasize that anti-VEGF treatment should be selected carefully in AMD patients with preexistent extensive RPE atrophy. |
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Keywords: | Ranibizumab RPE VEGF-A VEGFR-2 Oxidative stress |
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