VEGF regulates local inhibitory complement proteins in the eye and kidney

• Published in: The Journal of clinical investigation 2017-01, Vol.127 (1), p.199-214
• Main Authors: Keir, Lindsay S, Firth, Rachel, Aponik, Lyndsey, Feitelberg, Daniel, Sakimoto, Susumu, Aguilar, Edith, Welsh, Gavin I, Richards, Anna, Usui, Yoshihiko, Satchell, Simon C, Kuzmuk, Valeryia, Coward, Richard J, Goult, Jonathan, Bull, Katherine R, Sharma, Ruchi, Bharti, Kapil, Westenskow, Peter D, Michael, Iacovos P, Saleem, Moin A, Friedlander, Martin
• Format: Article
• Language: English
• Subjects: Aged; Analysis; Animals; Biomedical research; Colleges & universities; Complement Factor H - genetics; Complement Factor H - metabolism; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Edema; Experiments; Eye Proteins - antagonists & inhibitors; Eye Proteins - genetics; Eye Proteins - metabolism; Female; Humans; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - pathology; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - metabolism; Macular Degeneration - pathology; Male; Medical research; Mice; Mice, Knockout; Neovascularization; Patients; Photoreceptors; Podocytes - metabolism; Podocytes - pathology; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; Proteins; Research centers; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Rodents; Thrombotic Microangiopathies - genetics; Thrombotic Microangiopathies - metabolism; Thrombotic Microangiopathies - pathology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI86418

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.