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Lindsay S Keir, Peter D Westenskow, Yoshihiko Usui, Toshihide Kurihara, Anna Richards, Moin Saleem, Martin Friedlander; Vascular endothelial growth factor (VEGF) enhances retinal pigmented epithelial (RPE) cell production of protective complement factor H. Invest. Ophthalmol. Vis. Sci. 2014;55(13):68.
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The complement factor H (CFH) polymorphism Y402H is linked with age related macular degeneration (AMD) but it is unclear how this contributes to disease pathogenesis. VEGF antagonists are often used to treat neovascularization associated with exudative AMD. However, loss of RPE cell VEGF leads to degeneration of the choriocapillaris and vision loss. Furthermore, some patients treated with these drugs, as well as mice with a glomerular specific VEGF knockout, develop renal complications such as hemolytic uremic syndrome (HUS). Mutations in CFH are also associated with atypical HUS. We hypothesized based on previous work in the kidney that VEGF regulates RPE CFH synthesis and loss of VEGF decreases RPE CFH making the outer retina vulnerable to complement mediated cell damage.
Human ARPE-19 and fetal RPE cells were analysed for CFH expression and synthesis before and after VEGF treatment. The eyes of inducible RPE-specific VEGF and VHL knockout mice were analysed for CFH expression and evidence of complement deposition. Human eyes from AMD patients and controls were analysed for CFH expression and complement activation.
RPE cells synthesized CFH in vitro, and VEGF significantly increased CFH expression in a dose dependent manner. CFH was also detected in the RPE and choriocapillaris of wild type mice. CFH levels were attenuated after conditional ablation of VEGF in adult mice, and enhanced after inducing VEGF overexpression by deleting VHL. Evidence of complement activation and reduced retinal CFH expression was observed in AMD donor eyes when compared with control samples.
The RPE synthesizes CFH that is protective against complement-meditated damage and its synthesis is up regulated by VEGF. Loss of RPE-derived VEGF leads to reduced levels of CFH in mice. Evidence of local complement activation and reduced CFH in the outer retina was detected in AMD patients. Therefore, anti-VEGF treatment may lead to a reduction in RPE- derived CFH and, thus, enhance local complement activation. This could be detrimental even in AMD patients without the CFH polymorphism. Further work is needed to fully assess the effect of VEGF inhibition on local complement proteins not only in the eye but in other organ systems. This could help improve our understanding of AMD pathogenesis and its treatment, leading to more targeted therapies.
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