Retinal iron accumulation and degeneration in mice with high blood iron levels

Abstract

Purpose : Hepcidin (Hepc) regulates systemic iron levels by triggering the degradation of the iron exporter, ferroportin (Fpn). Hepc is primarily produced by the liver and secreted into the bloodstream, where it prevents Fpn-mediated iron transfer from the gut to the blood. The retina also produces Hepc. We have previously shown that systemic Hepc KO causes retinal iron overload and degeneration. However, the role of retina-produced Hepc in regulation of retinal iron levels is largely unknown. Herein, we test whether liver-produced Hepc affects the retina.

Methods : To determine the role of Hepc in retinal iron regulation, we used a liver-specific Hepc KO model (Hepc^f/f, AlbCre+), which has elevated blood and liver iron levels, and compared retinal iron levels in these mice to controls (Hepc^+/+, AlbCre+) and to systemic Hepc KO (Hepc^-/-) mice. Mice were aged to 6mo and systemic and retinal iron levels were analyzed using Perls’ iron stain, qPCR, and ICP-MS. Retinal structure and morphology were tested by in vivo imaging and histology.

Results : Retinal iron levels were elevated in both the conditional KO and Hepc^-/- compared to controls. However, the largest increase in iron levels occurred in the RPE of conditional KOs. Elevated retinal iron in the conditional KOs occurred despite an increase in retina-produced Hepc (Fig 1). Elevated retinal iron levels in the conditional KO lead to the development of RPE autofluoresence and hypertrophy (Fig 2).

Conclusions : The observed increase in retina-produced Hepc is insufficient to prevent retinal iron loading in the context of high blood iron levels present in the liver-specific Hepc KO mice. In fact, it may explain the increased RPE iron loading in conditional KO mice compared to Hepc^-/- mice; retina-produced Hepc may trap iron in the RPE. These data suggest that blood iron levels are an important determinant of retinal iron levels. The current study emphasizes the need to assess the impact of dietary and supplemental iron intake on retinal health.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

 

Fig 1. Perls’-stained Hepc^+/+,AlbCre+(A), Hepc^f/f,AlbCre+(B) and Hepc^-/-(C) retinas. Hepc^f/f,AlbCre+ mice accumulated iron in RPE (arrows). There was increased Hepc (Hamp) mRNA in retinas of the Hepc^f/f, AlbCre+ mice compared to controls (D).

 

Fig 2. Funduscopic images demonstrate lipofuscin autofluorescence in the conditional KO mice (B). Plastic sections demonstrate focal areas of RPE hypertrophy in the conditional KO mice (E,arrows).