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

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 1 2011

Fingerprint

Hepcidins
Knockout Mice
Iron
Retina
Endothelial Cells
Retinal Degeneration
Intravitreal Injections
Blood-Retinal Barrier
Photometry
Retinal Diseases
Messenger RNA
Peptide Hormones
Extracellular Signal-Regulated MAP Kinases

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Hadziahmetovic, M., Song, Y., Ponnuru, P., Iacovelli, J., Hunter, A., Haddad, N., ... 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
Hadziahmetovic, Majda ; Song, Ying ; Ponnuru, Padmavathi ; Iacovelli, Jared ; Hunter, Allan ; Haddad, Nadine ; Beard, John ; Connor, James R. ; Vaulont, Sophie ; Dunaief, Joshua L. / Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice. In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 1. pp. 109-118.
@article{c16a2fbde08a4be3bb8e1b9fbfbb0250,
title = "Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice",
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.",
author = "Majda Hadziahmetovic and Ying Song and Padmavathi Ponnuru and Jared Iacovelli and Allan Hunter and Nadine Haddad and John Beard and Connor, {James R.} and Sophie Vaulont and Dunaief, {Joshua L.}",
year = "2011",
month = "1",
day = "1",
doi = "10.1167/iovs.10-6113",
language = "English (US)",
volume = "52",
pages = "109--118",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "1",

}

Hadziahmetovic, M, Song, Y, Ponnuru, P, Iacovelli, J, Hunter, A, Haddad, N, Beard, J, Connor, JR, Vaulont, S & Dunaief, JL 2011, 'Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice', Investigative Ophthalmology and Visual Science, vol. 52, no. 1, pp. 109-118. https://doi.org/10.1167/iovs.10-6113

Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice. / Hadziahmetovic, Majda; Song, Ying; Ponnuru, Padmavathi; Iacovelli, Jared; Hunter, Allan; Haddad, Nadine; Beard, John; Connor, James R.; Vaulont, Sophie; Dunaief, Joshua L.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 1, 01.01.2011, p. 109-118.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice

AU - Hadziahmetovic, Majda

AU - Song, Ying

AU - Ponnuru, Padmavathi

AU - Iacovelli, Jared

AU - Hunter, Allan

AU - Haddad, Nadine

AU - Beard, John

AU - Connor, James R.

AU - Vaulont, Sophie

AU - Dunaief, Joshua L.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79952227908&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952227908&partnerID=8YFLogxK

U2 - 10.1167/iovs.10-6113

DO - 10.1167/iovs.10-6113

M3 - Article

C2 - 20811044

AN - SCOPUS:79952227908

VL - 52

SP - 109

EP - 118

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 1

ER -