Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice.
OBJECTIVE
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 spectrophotometry, Perls' iron stain, and immunofluorescence to assess iron-handling proteins. 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 autofluorescent RPE, photoreceptor death, and subretinal neovascularization. Hepc(-/-) mice had increased Fpn immunoreactivity 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 regulation. 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 regulation.
Hadziahmetovic
Majda
M
University of Pennsylvania, Philadelphia, PA, USA.
Song
Ying
Y
Ponnuru
Padmavathi
P
Iacovelli
Jared
J
Hunter
Allan
A
Haddad
Nadine
N
Beard
John
J
Connor
James R
JR
Vaulont
Sophie
S
Dunaief
Joshua L
JL
D000375:Aging / Q000502:physiology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D005453:Fluorescence; D019084:Fluorescent Antibody Technique, Indirect; D064451:Hepcidins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology; D013054:Spectrophotometry, Atomic; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000098742:Ferroportin; D001052:Apoferritins
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