VEGF regulates local inhibitory complement proteins in the eye and kidney
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2016
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| _version_ | 1826274090731700224 |
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| author | Keir, L Firth, R Aponik, L Feitelberg, D Sakimoto, S Aguilar, E Welsh, G Richards, A Usui, Y Satchell, S Kuzmuk, V Coward, R Goult, J Bull, K Sharma, R Bharti, K Westenskow, P Michael, I Saleem, M Friedlander, M |
| author_facet | Keir, L Firth, R Aponik, L Feitelberg, D Sakimoto, S Aguilar, E Welsh, G Richards, A Usui, Y Satchell, S Kuzmuk, V Coward, R Goult, J Bull, K Sharma, R Bharti, K Westenskow, P Michael, I Saleem, M Friedlander, M |
| author_sort | Keir, L |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:38:08Z |
| format | Journal article |
| id | oxford-uuid:5a9ea057-38c3-46bc-9570-f5709ae0c1b8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:38:08Z |
| publishDate | 2016 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:5a9ea057-38c3-46bc-9570-f5709ae0c1b82022-03-26T17:17:00ZVEGF regulates local inhibitory complement proteins in the eye and kidneyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5a9ea057-38c3-46bc-9570-f5709ae0c1b8EnglishSymplectic Elements at OxfordAmerican Society for Clinical Investigation2016Keir, LFirth, RAponik, LFeitelberg, DSakimoto, SAguilar, EWelsh, GRichards, AUsui, YSatchell, SKuzmuk, VCoward, RGoult, JBull, KSharma, RBharti, KWestenskow, PMichael, ISaleem, MFriedlander, MOuter 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. |
| spellingShingle | Keir, L Firth, R Aponik, L Feitelberg, D Sakimoto, S Aguilar, E Welsh, G Richards, A Usui, Y Satchell, S Kuzmuk, V Coward, R Goult, J Bull, K Sharma, R Bharti, K Westenskow, P Michael, I Saleem, M Friedlander, M VEGF regulates local inhibitory complement proteins in the eye and kidney |
| title | VEGF regulates local inhibitory complement proteins in the eye and kidney |
| title_full | VEGF regulates local inhibitory complement proteins in the eye and kidney |
| title_fullStr | VEGF regulates local inhibitory complement proteins in the eye and kidney |
| title_full_unstemmed | VEGF regulates local inhibitory complement proteins in the eye and kidney |
| title_short | VEGF regulates local inhibitory complement proteins in the eye and kidney |
| title_sort | vegf regulates local inhibitory complement proteins in the eye and kidney |
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