A High Serum Iron Level Causes Mouse Retinal Iron Accumulation Despite an Intact Blood-Retinal Barrier

Zhao, Lingling; Li, Yafeng; Song, Delu; Song, Ying; Theurl, Milan; Wang, Chenguang; Cwanger, Alyssa; Su, Guanfang; Dunaief, Joshua L.

doi:10.1016/j.ajpath.2014.07.008

Cited by 21 publications

(25 citation statements)

References 22 publications

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“…In the setting of high intracellular labile iron levels, Ft-L transcription and translation are increased, whereas Tfrc mRNA stability is decreased (Gárate and Núñez, 2000). These phenomena have been observed previously in retinal iron overload mouse models and RPE cell culture studies (Hahn et al PNAS 2004; Li et al, 2015; Zhao et al, 2014). After two weekly iron-sucrose injections, the NSR of +Fe mice had similar Ft-L and Tfrc mRNA levels compared to controls (Figure 1A,B).…”

Section: Resultssupporting

confidence: 81%

“…Relative to controls, Ft-L mRNA was significantly increased and transferrin receptor mRNA was decreased in the RPE but not the NSR in +Fe mice. Our interpretation of these data is that the blood-retinal barrier protects against influx of iron from the serum to the inner retina but not to the RPE—as the RPE itself is a component of the barrier (Bhoiwala et al, 2015; Zhao et al, 2014). …”

Section: Discussionmentioning

confidence: 97%

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AMD-like retinopathy associated with intravenous iron

Song

Kanu

et al. 2016

Experimental Eye Research

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Iron accumulation in the retina is associated with the development of age-related macular degeneration (AMD). IV iron is a common method to treat iron deficiency anemia in adults, and its retinal manifestations have not hitherto been identified. To assess whether IV iron formulations can be retina-toxic, we generated a mouse model for iron-induced retinal damage. Male C57BL/6J mice were randomized into groups receiving IV iron-sucrose (+Fe) or 30% sucrose (−Fe). Iron levels in neurosensory retina (NSR), retinal pigment epithelium (RPE), and choroid were assessed using immunofluorescence, quantitative PCR, and the Perls’ iron stain. Iron levels were most increased in the RPE and choroid while levels in the NSR did not differ significantly in +Fe mice compared to controls. Eyes from +Fe mice shared histological features with AMD, including Bruch’s membrane (BrM) thickening with complement C3 deposition, as well as RPE hypertrophy and vacuolization. This focal degeneration correlated with areas with high choroidal iron levels. Ultrastructural analysis provided further detail of the RPE/photoreceptor outer segment vacuolization and Bruch’s membrane thickening. Findings were correlated with a clinical case of a 43-year-old patient who developed numerous retinal drusen, the hallmark of AMD, within 11 months of IV iron therapy. Our results suggest that IV iron therapy may have the potential to induce or exacerbate a form of retinal degeneration. This retinal degeneration shares features with AMD, indicating the need for further study of AMD risk in patients receiving IV iron treatment.

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 97%

AMD-like retinopathy associated with intravenous iron

Song

Kanu

et al. 2016

Experimental Eye Research

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“…A BMP‐6 gene knockout mouse model exhibited age‐related iron accumulation and retinal degeneration. Elevated serum iron levels affected the level of retinal oxidative stress (Zhao et al, ). The direct effect of BMP‐6 on RPE cells and its regulatory mechanism on iron metabolism are not clear.…”

Section: Discussionmentioning

confidence: 99%

H₂O₂ induces oxidative stress damage through the BMP‐6/SMAD/hepcidin axis

Chen

et al. 2020

Dev Growth Differ

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Age-related macular degeneration (AMD) is one of the leading causes of blindness in elderly individuals worldwide. Oxidative stress injury to retinal pigment epithelial (RPE) cells plays a major role in the pathogenesis of AMD. The purpose of this study was to observe the correlation between Hepcidin and neovascular age-related macular degeneration (nAMD) and to further observe whether oxidative stress can inhibit Hepcidin expression through relevant signaling pathways to produce oxidative damage. We compared the concentrations of Hepcidin in the aqueous humor of nAMD patients and a control group and found that the concentration of Hepcidin was lower in nAMD patients. Through PCR and western blotting, we observed that H 2 O 2 can significantly inhibit the expression of Bone morphogenetic protein-6 (BMP-6) andHepcidin and increase the intracellular iron concentration in RPE cells, while BMP-6 can reverse the inhibition of Hepcidin and the increase in iron concentration caused by H 2 O 2 . In addition, alterations in smad1 and smad5 expression were examined, and pretreatment with BMP-6 was demonstrated to reduce H 2 O 2 -induced activation of smad1 and smad5. The effects of BMP-6 were attenuated by smad1 and smad5 siRNA, further verifying that oxidative stress inhibits the expression of Hepcidin by inhibiting activation of the BMP/SMAD signaling pathway. To some extent, this study verified that oxidative stress injury plays a role in nAMD by affecting the level of hepcidin, which lays a foundation for exploring new methods to treat nAMD. K E Y W O R D Sbone morphogenetic protein-6, H 2 O 2 , Hepcidin, neovascular age-related macular degeneration

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“…If the RPE behaved like other phagocytosing cells and increased Fpn expression in the hepcidin KO mice, the RPE may not become iron overloaded. Accordingly, RPE iron overload in hepcidin KO mice and Fpn C326S mice (which also have increased systemic iron levels), and after systemic iron injections (29) could be explained by failure to up‐regulate basolateral RPE Fpn.…”

Section: Discussionmentioning

confidence: 99%

Mice with hepcidin‐resistant ferroportin accumulate iron in the retina

et al. 2015

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Because ferroportin (Fpn) is the only known mammalian cellular iron exporter, understanding its localization and regulation within the retina would shed light on the direction of retinal iron flux. The hormone hepcidin may regulate retinal Fpn, as it triggers Fpn degradation in the gut. Immunofluorescence was used to label Fpn in retinas of mice with 4 different genotypes (wild type; Fpn C326S, a hepcidin-resistant Fpn; hepcidin knockout; and ceruloplasmin/hephaestin double knockout). No significant difference in Fpn levels was observed in these retinas. Fpn localized to the abluminal side of the outer plexiform vascular endothelial cells, Müller glia cells, and the basolateral side of the retinal pigment epithelium. Adenoassociated virus (AAV)-hepcidin was injected into the eyes of hepcidin knockout mice, while AAV-lacZ was injected into the contralateral eyes as a control. AAV-hepcidin injected eyes had increased ferritin immunolabeling in retinal vascular endothelial cells. Fpn C326S mice had systemic iron overload compared to wild type and had the fastest retinal iron accumulation of any hereditary model studied to date. The results suggest that physiologic hepcidin levels are insufficient to alter Fpn levels within the retinal pigment epithelium and Müller cells, but may limit iron transport into the retina from vascular endothelial cells.-Theurl, M., Song, D., Clark, E., Sterling, J., Grieco, S., Altamura, S., Galy, B., Hentze, M., Muckenthaler, M. U., Dunaief, J. L. Mice with hepcidin-resistant ferroportin accumulate iron in the retina. FASEB J. 30, 813-823 (2016). www.fasebj.org Key Words: retinal pigment epithelium • vascular endothelium • iron transport • blood-brain barrier Iron, while essential for living organisms, must be tightly regulated as it can catalyze the formation of reactive oxygen species. Within the retina, labile iron has been shown to cause degeneration (1). Age-related macular degeneration (AMD), the leading cause of irreversible vision loss in individuals over 50 yr old (2), is associated with increased retinal iron (3). We have previously studied mice lacking the 2 ferroxidases ceruloplasmin (Cp) and hephaestin (Heph), which leads to intracellular iron entrapment. These double-knockout (DKO) mice develop retinal iron overload, causing retinal degeneration with some histologic and molecular features of human AMD (4). Retinal degeneration in the ceruloplasmin/hephaestin DKO (Cp/Heph DKO) mice can be ameliorated by systemic iron chelation therapy (5). A role for iron in AMD is further supported by the observation that patients with aceruloplasminemia, an autosomal recessive disease with retinal iron accumulation, can develop early-onset macular degeneration (6, 7).Ferroportin (Fpn), a transmembrane protein that is the only known cellular iron exporter (8), and hepcidin, an iron regulatory hormone, are 2 key contributors to retinal iron homeostasis. In enterocytes and macrophages, hepcidin binds to Fpn, triggering its internalization and degradation (9). Knockout (KO) of hepcidi...

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A High Serum Iron Level Causes Mouse Retinal Iron Accumulation Despite an Intact Blood-Retinal Barrier

Cited by 21 publications

References 22 publications

AMD-like retinopathy associated with intravenous iron

AMD-like retinopathy associated with intravenous iron

H₂O₂ induces oxidative stress damage through the BMP‐6/SMAD/hepcidin axis

Mice with hepcidin‐resistant ferroportin accumulate iron in the retina

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A High Serum Iron Level Causes Mouse Retinal Iron Accumulation Despite an Intact Blood-Retinal Barrier

Cited by 21 publications

References 22 publications

AMD-like retinopathy associated with intravenous iron

AMD-like retinopathy associated with intravenous iron

H2O2 induces oxidative stress damage through the BMP‐6/SMAD/hepcidin axis

Mice with hepcidin‐resistant ferroportin accumulate iron in the retina

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H₂O₂ induces oxidative stress damage through the BMP‐6/SMAD/hepcidin axis