Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice

Majda Hadziahmetovic, Ying Song, Padmavathi Ponnuru, Jared Iacovelli, Allan Hunter, Nadine Haddad, John Beard, James R. Connor, Sophie Vaulont, Joshua L. Dunaief

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60 Scopus citations

Abstract

Iron dysregulation can cause retinal disease, yet retinal iron regulatory mechanisms are incompletely understood. The peptide hormone hepcidin (Hepc) limits iron uptake from the intestine by triggering degradation of the iron transporter ferroportin (Fpn). Given that Hepc is expressed in the retina and Fpn is expressed in cells constituting the blood-retinal barrier, the authors tested whether the retina may produce Hepc to limit retinal iron import. Methods. Retinas of Hepc-/- mice were analyzed by histology, autofluorescence spectral analysis, atomic absorption spectro photometry, Perls' iron stain, and immunofluorescence to assess iron-handling prote ins. Retinal Hepc mRNA was evaluated through qPCR after intravitreal iron injection. Mechanisms of retinal Hepc upregulation were tested by Western blot analysis. A retinal capillary endothelial cell culture system was used to assess the effect of exogenous Hepc on Fpn. Results Hepc-/- mice experienced age-dependent increases in retinal iron followed by retinal degeneration with autofluo-rescent RPE, photoreceptor death, and subretinal neovascularization. Hepc-/- mice had increased Fpn immuno reactivity in vascular endothelial cells. Conversely, in cultured retinal capillary endothelial cells, exogenous Hepc decreased both Fpn levels and iron transport. The retina can sense increased iron levels, upregulating Hepc after phosphorylation of extracellular signal regulated kinases. Conclusions. These findings indicate that Hepc is essential for retinal iron regulateon. In the absence of Hepc, retinal degeneration occurs. Increases in Hepc mRNA levels after intravitreal iron injection combined with Hepc-mediated decreases in iron export from cultured retinal capillary endothelial cells suggest that the retina may use Hepc for its tissue-specific iron.

Original languageEnglish (US)
Pages (from-to)109-118
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number1
DOIs
StatePublished - Jan 2011

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Hadziahmetovic, M., Song, Y., Ponnuru, P., Iacovelli, J., Hunter, A., Haddad, N., Beard, J., Connor, J. R., Vaulont, S., & Dunaief, J. L. (2011). Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice. Investigative Ophthalmology and Visual Science, 52(1), 109-118. https://doi.org/10.1167/iovs.10-6113