VEGF regulates local inhibitory complement proteins in the eye and kidney
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lar CFH staining (Figure 1A, controls shown in Supplemental Figure 1, A-C; supplemental material available online with this article; doi:10.1172/JCI86418DS1),and glomerular deposits of C3 that were suggestive of complement activity (Figure 1B).To further examine these results, human glomerular endothelial cells and podocytes were studied and were shown to synthesize inhibitory CFH in response to VEGF in a dose-dependent manner (Figure 1C).The production of CFH was confirmed by Western blotting (Figure 1D, cell lysate; Figure 1E, condition media) and by quantitative PCR (qPCR) using CFH-specific primers (Figure 1F).VEGF did not have this effect on CFH in other endothelial and control cell lines, suggesting the observations were specific to the glomerular cells (Figure 1C, HUVEC and HEK293 panels).Furthermore, 24 hours of VEGF pretreatment reduced complement deposition on these cells after in vitro complement activation (Figure 1G).This suggests that the VEGF-induced changes were functionally relevant.CFH is considered the most important inhibitor of the alternative pathway (30).To determine why VEGF also reduced C4/ C4d deposition (Supplemental Figure 1, D and E), we studied other complement regulators.In the glomeruli of mice with inducible, podocyte-specific Vegfa deletion, CD59a was also reduced, but CD55 and Crry were not (Supplemental Figure 1, F-H).CD46 was not examined in mice, since it is only expressed in the testes (31).Human glomerular endothelial cells expressed more CD59 and CD46, but not CD55, after VEGF treatment (Supplemental Figure 1, I-K).These effects were dose dependent.Similarly, in primary human RPE cells, VEGF caused a dose-dependent increase of CFH and CD46, but not CD55 (Figure 2, A-C and Supplemental Figure 2, A and B), with reduced complement deposits (Figure 2D and Supplemental Figure 2C).The same results were obtained from ARPE19 cells, but only primary human RPE cell data are shown here.VEGF antagonism using bevacizumab or the fab fragment ranibizumab reduced CFH and CD46 expression (Figures 2, A-C and Supplemental Figure 2, A and B) and increased C3d and C4d deposits (Figure 2D and Supplemental Figure 2C).The doses of VEGF antagonist used were comparable to those given to patients by intravitreal injection.To determine whether these effects also occurred in vivo, RPE-induced Vegfa knockout was accomplished in adult mice using VMD2-Cre.These mice showed severe choriocapillaris attenuation (4) and, similarly to mice with inducible, podocyte-specific Vegfa, complement inhibitors CFH and CD59a were reduced 3 days after induction (Figure 2, E and F, and Supplemental Figure 2D).Reduction in VEGF was confirmed in choroid/RPE sections from RPE-induced Vegfa-knockout mice (Figure 2G).These same sections showed increased C5b-9 levels compared with controls, showing that they had increased complement activation (Figure 2H).Conversely, 3 days after RPE-induced Vhl knockout, which causes pseudohypoxia and increased RPE-derived VEGF (32), more CFH was detected (Supplemental Figure 2E).These effects were not limited to the outer retina.Other sources of retinal VEGF are amacrine and horizontal cells, lateral interneurons that associate with intraretinal capillaries (10).When Vegfa and Vhl were knocked out of these neurons, similar changes in CFH were detected in the inner retina, showing an in vivo dose response (Supplemental Figure 2, F and G).Reductions in CD55 and CD59a, but not Crry, were also noted in these mice (Supplemental Figure 2H).These results jci.org
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VEGF inhibition has been shown to increase complement activation by decreasing FH expression in RPE and renal podocytes through VEGFR2- and PKC-α/CREB-dependent signalling.
“It is worth noting that the VEGF–complement interaction may also be reciprocal; VEGF inhibition has been shown to increase complement activation by decreasing FH expression in RPE and renal podocytes through VEGFR2- and PKC-α/CREB-dependent signalling [168].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [168]
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Effects of bevacizumab in retina and choroid after intravitreal injection into monkey eyes
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Cloning and analysis of the human complement factor H gene promoter
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Effect of VEGF and anti-VEGF Compounds on Retinal Pigment Epithelium Permeability: An in Vitro Study
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Tan WH, Popel AS, Mac Gabhann F. Computa- tional model of VEGFR2 pathway to ERK activa- tion and modulation through receptor traffick- ing. Cell Signal. 2013;25(12):2496-2510.
Cited by
Sorted by citations
Li, W., Song, Y., Chen, K., Ying, J., Zheng, Z., Qiao, S., Yang, M., Zhang, M., & Zhang, Y. (2021) · BMJ Open · doi:10.1136/bmjopen-2021-050989 · Cited by 76 · see citing works
Implications of genetic variation in the complement system in age-related macular degeneration
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Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44 · see citing works
- Authors
- 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.
- Affiliations
- Scripps Research Institute (US)
- University of Bristol (GB)
- The Queen's Medical Research Institute (GB)
- University of Oxford (GB)
- National Institutes of Health (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Friedlander, Martin
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-12-05
- Volume
- 127
- Issue
- 1
- Pages
- 199-214
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5199702
- OpenAlex
- W2559556008
- Cited by
- 154
- References
- 93
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 17 · 2023: 16 · 2022: 17 · 2021: 18 · 2020: 16 · 2019: 18 · 2018: 16 · 2017: 12 · 2016: 1
- FWCI
- 9.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Explore Bristol Research (submittedVersion, cc-by)
- National University of Singapore (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Funders
- Wellcome Trust (WT085226)
- Lowy Medical Research Institute
- National Institute for Health and Care Research (CL-2013-25-002)
- Kidney Research UK (RP45/2008, ST_004_20151126, RP22/2012)
- Academy of Medical Sciences (AMS-SGCL13-Bull)
- University of Bristol
- National Institutes of Health
- Medical Research Council (MR/L002418/1, MR/K010492/1)
- Japan Society for the Promotion of Science (16K11330)
- National Eye Institute (R01EY011254)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- vascular endothelial growth factor, complement regulation, complement factor H, CD46, CD59, alternative complement pathway, glomerular endothelial cells, podocytes, retinal pigment epithelium, complement deposition, bevacizumab, ranibizumab, anti-VEGF therapy, glaucoma, diabetic retinopathy, diabetic nephropathy
- MeSH terms
- Aged, Animals, Eye Proteins, Female, Humans, Kidney Diseases, Macular Degeneration, Male, Complement Factor H, Cyclic AMP Response Element-Binding Protein, Mice, Knockout, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Podocytes, Mice, Protein Kinase C-alpha, Retinal Pigment Epithelium, Thrombotic Microangiopathies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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