VEGF regulates local inhibitory complement proteins in the eye and kidney

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

Research output: Contribution to journalArticle (Academic Journal)

50 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)199-214
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number1
Early online date5 Dec 2016
DOIs
Publication statusPublished - 3 Jan 2017

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    Keir, L. S., Firth, R., Aponik, L., Feitelberg, D., Sakimoto, S., Aguilar, E., Welsh, G. I., Richards, A., Usui, Y., Satchell, S. C., Kuzmuk, V., Coward, R. J., Goult, J., Bull, K. R., Sharma, R., Bharti, K., Westenskow, P. D., Michael, I. P., Saleem, M. A., & Friedlander, M. (2017). VEGF regulates local inhibitory complement proteins in the eye and kidney. Journal of Clinical Investigation, 127(1), 199-214. https://doi.org/10.1172/JCI86418