Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Zarbin, Marco A.

doi:10.1001/archopht.122.4.598

Cited by 913 publications

(736 citation statements)

References 210 publications

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“…Chronic retinal inflammation in humans is expected to cause iron overload within the retina, but whether such effects have any relevance to the pathogenesis of age-related macular degeneration remains to be seen. It is interesting to note that genetic variations in genes involved in inflammation and oxidative stress, including the Toll-like receptor-4 [43], have been implicated in the pathogenesis of age-related macular degeneration [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

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SummaryHepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells, and retinal pigment epithelium (RPE) within the retina. Since the retina is protected by the retinal-blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells, and RPE, closely resembling the expression pattern of ferroportin. We also show that bacterial lipopolysaccharide (LPS) is a regulator of hepcidin expression in Müller cells and RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the Toll-like receptor-4. The upregulation of hepcidin by LPS occurs independent of Hfe (Human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent downregulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.

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Section: Discussionmentioning

confidence: 99%

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Gnana-Prakasam

Martin

Mysona

et al. 2008

Biochemical Journal

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“…There is interest in the use of nutrition as a prevention and treatment strategy for age-related macular disease (ARMD) as it is the leading cause of visual disability in the developed World (Klein et al, 1997), and because treatment options are currently lacking (Zarbin, 2004). According to an international classification and grading system (Bird et al, 1995), this condition can be divided into early (age-related maculopathy, (ARM)) and late (age-related macular degeneration, (AMD)) stages.…”

Section: Introductionmentioning

confidence: 99%

Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial

Bartlett

Eperjesi

2007

Eur J Clin Nutr

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Objective: The aim of the study is to determine the effect of lutein combined with vitamin and mineral supplementation on contrast sensitivity in people with age-related macular disease (ARMD). Design: A prospective, 9-month, double-masked randomized controlled trial. Setting: Aston University, Birmingham, UK and a UK optometric clinical practice. Subjects: Age-related maculopathy (ARM) and atrophic age-related macular degeneration (AMD) participants were randomized (using a random number generator) to either placebo (n ¼ 10) or active (n ¼ 15) groups. Three of the placebo group and two of the active group dropped out. Interventions: The active group supplemented daily with 6 mg lutein combined with vitamins and minerals. The outcome measure was contrast sensitivity (CS) measured using the Pelli-Robson chart, for which the study had 80% power at the 5% significance level to detect a change of 0.3 log units. Results: The CS score increased by 0.0770.07 and decreased by 0.0270.18 log units for the placebo and active groups, respectively. The difference between these values is not statistically significant (z ¼ À0.903, P ¼ 0.376). Conclusion:The results suggest that 6 mg of lutein supplementation in combination with other antioxidants is not beneficial for this group. Further work is required to establish optimum dosage levels.

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“…The mechanism of this disease remains elusive and current therapeutic options are limited. An increasing body of literature indicates that development of AMD is related to dysfunction of RPE (Boulton et al, 2004;Zarbin, 2004;Zhou et al, 2005). One essential function of the postmitotic RPE is phagocytosis and degradation of shed photoreceptor outer segments.…”

Section: Introductionmentioning

confidence: 99%

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

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As in many other types of cells, retinal pigment epithelial (RPE) cells have an active ubiquitineproteasome pathway (UPP). However, the function of the UPP in RPE remains to be elucidated. The objective of this study is to determine the role of the UPP in controlling the levels and activities of transcription factors hypoxia-inducible factor (HIF) and NF-kB. We inhibited the UPP with proteasome-specific inhibitors and determined the activation of HIF and NF-kB as well as the expression and secretion of pro-angiogenic factors. HIF-1a was not detectable in ARPE-19 cells under normal culture conditions. However, when proteasome activity was inhibited, HIF-1a accumulated in RPE in a time-dependent manner. Consistent with accumulation of HIF-1a in the cells, levels of mRNA for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in RPE were up to 7-fold higher upon inhibition of the proteasome. Proteasome inhibition was also associated with a 2-fold increase in levels of mRNA for angiopoietin-1 (Ang-1). ARPE-19 cells secrete significant levels of VEGF under normal culture conditions. Inhibition of proteasome activity increased the secretion of VEGF by 2-fold. In contrast to the increase in HIF activity, NF-kB activation was reduced by proteasome inhibition. In addition, the expression and secretion of monocyte chemoattractant protein-1 (MCP-1) by RPE were substantially attenuated by the inhibition of proteasome activity. These data demonstrate that the UPP plays an important role in modulating the activities of HIF and NF-kB in the RPE. Consequences of an impairment of the UPP include accumulation of HIF-1a and diminished NF-kB activation, which lead to enhanced expression and secretion of pro-angiogenic factors and attenuated expression of MCP-1. Taken together, these data predict that the impairment of the UPP could lead to the development of AMD-related phenotypes.

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Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Cited by 913 publications

References 210 publications

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

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