title: Ranibizumab interacts with the VEGF-A/VEGFR-2 signaling pathway in human RPE cells at different levels.
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.
authors.affiliation: Department of Ophthalmology, University of Lübeck, Germany; Laboratory for Angiogenesis & Ocular Cell Transplantation, University of Lübeck, Germany. Electronic address: eye.research101@gmail.com.
authors.forename: Mahdy
authors.initials: M
authors.lastname: Ranjbar
authors.affiliation: Department of Ophthalmology, University of Lübeck, Germany; Laboratory for Angiogenesis & Ocular Cell Transplantation, University of Lübeck, Germany. Electronic address: maxphilipp.brinkmann@uksh.de.
authors.forename: Max Philipp
authors.initials: MP
authors.lastname: Brinkmann
authors.affiliation: Department of Ophthalmology, University of Lübeck, Germany. Electronic address: ayseguel.tura@uksh.de.
authors.forename: Aysegül
authors.initials: A
authors.lastname: Tura
authors.affiliation: Department of Ophthalmology, University of Lübeck, Germany. Electronic address: mirudolf@aol.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Rudolf
authors.affiliation: Department of Ophthalmology, University of Lübeck, Germany; Institute of Biomedical Optics, University of Lübeck, Germany. Electronic address: miura@bmo.uni-luebeck.de.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Department of Ophthalmology, University of Lübeck, Germany. Electronic address: salvatore.grisanti@uksh.de.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grisanti
mesh_terms: D002460:Cell Line; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D000069579:Ranibizumab / Q000493:pharmacokinetics / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000069579:Ranibizumab
keywords: Oxidative stress; RPE; Ranibizumab; VEGF-A; VEGFR-2