Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration

Zeng, Siyuan; Whitmore, S. Scott; Sohn, Elliott H.; Riker, Megan; Wiley, Luke A; Scheetz, Todd E.; Stone, Edwin M.; Tucker, Budd A.; Mullins, Robert F.

doi:10.1002/path.4669

Cited by 51 publications

(67 citation statements)

References 45 publications

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“…FADS1 and FADS2 expression is also decreased in chorioretinal endothelial cells after formation of a complement membrane attack complex [49], a major risk factor for AMD [50]. These studies suggest that FADS1 and FADS2 may have important physiological functions in RPE-choroid of AMD.…”

Section: Discussionmentioning

confidence: 70%

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Ashikawa

Nishimura

Okabe

et al. 2017

Heliyon

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Age-related macular degeneration (AMD) is the most common cause of vision loss in elderly individuals throughout the developed world. Inhibitors of vascular endothelial growth factor have been successfully used to treat choroidal neovascularization in late-stage AMD. The pathogenesis of early-stage AMD, however, remains largely unknown, impairing efforts to develop effective therapies that prevent progression to late-stage AMD. To address this, we performed comparative transcriptomics of macular and extramacular retinal pigmented epithelium-choroid (RPE-choroid) tissue from early-stage AMD patients. We found that expression of fatty acid desaturase 1 (FADS1), FADS2, and acetyl-CoA acetyltransferase 2 (ACAT2) is increased in macular but not extramacular tissue, possibly through activation of sterol regulatory element binding factor 1 (SREBF1). Consistent with this, we also found that expression of Fads1 is increased in RPE-choroid in a mouse model of early-stage AMD. In zebrafish, deletion of fads2, which encodes a protein that functions as both Fads1 and Fads2 in other species, enhanced apoptosis in the retina upon exposure to intense light. Similarly, pharmacological inhibition of Srebf1 enhanced apoptosis and reduced fads2 expression in zebrafish exposed to intense light. These results suggest that the SREBF1–FADS1/2 axis may be activated in macular RPE-choroid as a protective response during early-stage AMD and could thus be a therapeutic target for early-stage AMD.

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Section: Discussionmentioning

confidence: 70%

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Ashikawa

Nishimura

Okabe

et al. 2017

Heliyon

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“…The reason why these patients respond less well is unclear, but could suggest a relationship between VEGF and complement. This is supported by reports that choriocapillaris endothelial cell loss is an early feature of ARMD (20, 21) and that this is associated with increased deposition of complement membrane attack complexes (MACs) (21, 22). …”

Section: Introductionmentioning

confidence: 61%

VEGF regulates local inhibitory complement proteins in the eye and kidney

Keir¹,

Firth²,

Aponik³

et al. 2016

Journal of Clinical Investigation

118

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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.

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“…Activation of the complement membrane attack complex (MAC) is strongest in the choriocapillaris of AMD donor eyes relative to age-matched healthy controls [18]. A cell culture study of a rhesus chorioretinal EC line suggests that MAC deposition may contribute to AMD pathogenesis via induction of characteristic phenotypes of choroidal endothelium in AMD, namely, a concomitant atrophy and proliferation [82]. CD59 is an important negative regulator of complement activation, which in mice protects the RPE/choroid from inflammatory damage [83] and may represent a putative therapeutic target for AMD [84, 85].…”

Section: Molecular and Cellular Consequences Of Choroidal Hemodynamicsmentioning

confidence: 99%

A Revised Hemodynamic Theory of Age-Related Macular Degeneration

Gelfand

Ambati

2016

Trends in Molecular Medicine

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Age-related macular degeneration (AMD) afflicts one out of every 40 individuals worldwide, causing irreversible central blindness in millions. The transformation of various tissue layers within the macula in the retina has led to competing conceptual models of the molecular pathways, cell types, and tissues responsible for the onset and progression of AMD. A model that has persisted for over 6 decades is the hemodynamic, or vascular theory of AMD progression, which states that vascular dysfunction of the choroid underlies AMD pathogenesis. Here, we re-evaluate this hypothesis in light of recent advances on molecular, anatomic, and hemodynamic changes underlying choroidal dysfunction in AMD. We propose an updated, detailed model of hemodynamic dysfunction as a mechanism of AMD development and progression.

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Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration

Cited by 51 publications

References 45 publications

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

VEGF regulates local inhibitory complement proteins in the eye and kidney

A Revised Hemodynamic Theory of Age-Related Macular Degeneration

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