Purchase this article with an account.
Jaya P Gnana-Prakasam, Kapil Chaudhary, Wanwisa Promsote, Sylvia B Smith, Vadivel Ganapathy, Pamela M Martin, Alan Saul; Retinal Iron Overload during Diabetic Retinopathy Accelerates Ganglion Cell Death. Invest. Ophthalmol. Vis. Sci. 2016;57(12):751.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Iron is required for normal function of many proteins in retina but excess iron can be toxic. So stringent mechanisms maintain iron levels by regulating proteins involved in iron homeostasis. Surprisingly, the potential role of impaired iron metabolism in diabetic retinopathy (DR) has not been elucidated. During DR, retina may accumulate iron due to inflammation and hemorrhage. Although there are reports on positive association between iron levels and proliferative retinopathies, the mechanism by which iron exacerbates this process is unknown. HFE, an important iron regulatory protein, senses cellular iron status and regulates iron uptake by competitively inhibiting transferrin receptor. We have previously reported that HFE is expressed in basolateral membrane of retinal pigment epithelium and HFE KO mice accumulate iron in retina with significant retinal degeneration by 18 months of age. In the present study, we induced diabetes in HFE knockout mice to understand the role of iron overload in the pathogenesis of DR.
Type I diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin. C57BLKS-Leprdb mice were used for type II diabetes. Iron levels in retina were measured by quantifying tissue levels of ferritin using ELISA, immunostaining and western blot. HFE WT and KO mice were made diabetic using streptozotocin. A group of WT and KO diabetic mice were treated orally with iron chelator deferiprone. Retinal phenotype was characterized using morphometric analysis, electroretinogram and immunostaining.
We found a marked increase in iron storage protein, ferritin, by ELISA, western blot and immunofluorescence in diabetic retina compared to control retina. Consistently, we found that HFE is upregulated in diabetic mice as well as in diabetic human retina. Also, diabetic HFE knockout mice had increased ganglion cell loss compared to diabetic wildtype mice by morphometric analysis, electroretinogram and immunostaining. Treatment with iron chelator, deferiprone, prevented neuronal cell death significantly.
Increase in retinal iron accumulation was evident in diabetic retina. Increased expression of HFE may indicate a regulatory mechanism in response to increase in retinal iron levels. Increased neuronal cell death in diabetic HFE knockout mice model of iron overload is an extremely novel finding indicating that iron overload can exacerbate the progression of DR.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
This PDF is available to Subscribers Only