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VEGF regulates local inhibitory complement proteins in the eye and kidney
Lindsay S. Keir, … , Moin A. Saleem, Martin Friedlander
Lindsay S. Keir, … , Moin A. Saleem, Martin Friedlander
Published December 5, 2016
Citation Information: J Clin Invest. 2017;127(1):199-214. https://doi.org/10.1172/JCI86418.
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Research Article Nephrology Ophthalmology

VEGF regulates local inhibitory complement proteins in the eye and kidney

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Abstract

Outer retinal and renal glomerular functions rely on specialized vasculature maintained by VEGF that is produced by neighboring epithelial cells, the retinal pigment epithelium (RPE) and podocytes, respectively. Dysregulation of RPE- and podocyte-derived VEGF is associated with neovascularization in wet age-related macular degeneration (ARMD), choriocapillaris degeneration, and glomerular thrombotic microangiopathy (TMA). Since complement activation and genetic variants in inhibitory complement factor H (CFH) are also features of both ARMD and TMA, we hypothesized that VEGF and CFH interact. Here, we demonstrated that VEGF inhibition decreases local CFH and other complement regulators in the eye and kidney through reduced VEGFR2/PKC-α/CREB signaling. Patient podocytes and RPE cells carrying disease-associated CFH genetic variants had more alternative complement pathway deposits than controls. These deposits were increased by VEGF antagonism, a common wet ARMD treatment, suggesting that VEGF inhibition could reduce cellular complement regulatory capacity. VEGF antagonism also increased markers of endothelial cell activation, which was partially reduced by genetic complement inhibition. Together, these results suggest that VEGF protects the retinal and glomerular microvasculature, not only through VEGFR2-mediated vasculotrophism, but also through modulation of local complement proteins that could protect against complement-mediated damage. Though further study is warranted, these findings could be relevant for patients receiving VEGF antagonists.

Authors

Lindsay S. Keir, Rachel Firth, Lyndsey Aponik, Daniel Feitelberg, Susumu Sakimoto, Edith Aguilar, Gavin I. Welsh, Anna Richards, Yoshihiko Usui, Simon C. Satchell, Valeryia Kuzmuk, Richard J. Coward, Jonathan Goult, Katherine R. Bull, Ruchi Sharma, Kapil Bharti, Peter D. Westenskow, Iacovos P. Michael, Moin A. Saleem, Martin Friedlander

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Figure 6

CFH genetic variants are less effective at regulating the alternative complement pathway.

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CFH genetic variants are less effective at regulating the alternative co...
Human iPS cells differentiated to RPE containing the ARMD CFH 402H polymorphism (ARMD cells) showed greater C3d deposits (C3d white, DAPI blue) compared with control cells when complement was activated on the cell surface (A, media, untreated column comparison). This effect was exacerbated by bevacizumab treatment (A, bevacizumab column comparison). There was no difference between cell types when C4d staining was analyzed at baseline without treatment or after bevacizumab (B, black lines denote comparison, C4d white, DAPI blue). However, bevacizumab significantly increased C4d deposits, and VEGF reduced these on both cell lines. The same effect was seen in podocytes after treatment with VEGF and bevacizumab for C3d (C, C3d white, DAPI blue) and C4d (D, C4d white, DAPI blue). Representative images from 4 independent experiments. Ten images obtained for each condition per individual experiment. Fluorescence was measured as MFI and corrected for cell number (semi-quantitative assessment). Two-way ANOVA. Statistics comparing the same cell types exposed to different treatments denoted as hatch marks. Statistics comparing different cell types denoted as NS or asterisks. #P < 0.05; ##P < 0.01; ###P < 0.001; *P < 0.05; ***P < 0.001; ****P < 0.0001. Black bars show which conditions were compared. Scale bars: 200 μm

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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