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VEGF regulates local inhibitory complement proteins in the eye and kidney

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VEGF regulates local inhibitory complement proteins in the eye and kidney. / 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.

In: Journal of Clinical Investigation, Vol. 127, No. 1, 03.01.2017, p. 199-214.

Research output: Contribution to journalArticle

Harvard

Keir, LS, Firth, R, Aponik, L, Feitelberg, D, Sakimoto, S, Aguilar, E, Welsh, GI, Richards, A, Usui, Y, Satchell, SC, Kuzmuk, V, Coward, RJ, Goult, J, Bull, KR, Sharma, R, Bharti, K, Westenskow, PD, Michael, IP, Saleem, MA & Friedlander, M 2017, 'VEGF regulates local inhibitory complement proteins in the eye and kidney', Journal of Clinical Investigation, vol. 127, no. 1, pp. 199-214. https://doi.org/10.1172/JCI86418

APA

Keir, L. S., Firth, R., Aponik, L., Feitelberg, D., Sakimoto, S., Aguilar, E., ... 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

Vancouver

Keir LS, Firth R, Aponik L, Feitelberg D, Sakimoto S, Aguilar E et al. VEGF regulates local inhibitory complement proteins in the eye and kidney. Journal of Clinical Investigation. 2017 Jan 3;127(1):199-214. https://doi.org/10.1172/JCI86418

Author

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. / VEGF regulates local inhibitory complement proteins in the eye and kidney. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 1. pp. 199-214.

Bibtex

@article{527f03451a2f4e98aa9309fb1fae30fc,
title = "VEGF regulates local inhibitory complement proteins in the eye and kidney",
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.",
author = "Keir, {Lindsay S} and Rachel Firth and Lyndsey Aponik and Daniel Feitelberg and Susumu Sakimoto and Edith Aguilar and Welsh, {Gavin I} and Anna Richards and Yoshihiko Usui and Satchell, {Simon C} and Valeryia Kuzmuk and Coward, {Richard J} and Jonathan Goult and Bull, {Katherine R} and Ruchi Sharma and Kapil Bharti and Westenskow, {Peter D} and Michael, {Iacovos P} and Saleem, {Moin A} and Martin Friedlander",
year = "2017",
month = "1",
day = "3",
doi = "10.1172/JCI86418",
language = "English",
volume = "127",
pages = "199--214",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "1",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - VEGF regulates local inhibitory complement proteins in the eye and kidney

AU - Keir, Lindsay S

AU - Firth, Rachel

AU - Aponik, Lyndsey

AU - Feitelberg, Daniel

AU - Sakimoto, Susumu

AU - Aguilar, Edith

AU - Welsh, Gavin I

AU - Richards, Anna

AU - Usui, Yoshihiko

AU - Satchell, Simon C

AU - Kuzmuk, Valeryia

AU - Coward, Richard J

AU - Goult, Jonathan

AU - Bull, Katherine R

AU - Sharma, Ruchi

AU - Bharti, Kapil

AU - Westenskow, Peter D

AU - Michael, Iacovos P

AU - Saleem, Moin A

AU - Friedlander, Martin

PY - 2017/1/3

Y1 - 2017/1/3

N2 - 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.

AB - 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.

U2 - 10.1172/JCI86418

DO - 10.1172/JCI86418

M3 - Article

VL - 127

SP - 199

EP - 214

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -