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Jaya Pranava Gnana-Prakasam, Sudha Ananth, Kapil Chaudhary, Vadivel Ganapathy, Sylvia B Smith, Pamela M Martin; Expression of Iron Regulatory Proteins in Diabetic Retina. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):154.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is the leading cause of blindness among adults in U.S. Dysregulation of local iron homeostasis has been implicated in several degenerative diseases due to oxidative stress induced by excess iron. Surprisingly, the potential role of impaired iron metabolism in the pathogenesis of DR has not been elucidated. Although iron is required for the normal function of many proteins in retina, excess iron can be toxic. Hence stringent mechanisms maintain iron levels by regulating proteins involved in iron homeostasis. HFE, an important iron regulatory protein, senses the cellular iron status and regulates hepcidin expression. Hepcidin in turn binds to iron exporting protein, ferroportin, and degrades it. In the present study, we examined the expression of iron regulatory genes in diabetic retina.
Type I diabetes was induced in C57BL/6 male mice by intraperitoneal injection of streptozotocin. B6.BKS-Leprdb mice were used as a model for type II diabetes. Expression of various iron-regulatory genes in diabetic mice and post-mortem human eyes were monitored by RT-PCR and immunofluorescence. Iron levels in control and diabetic retina were measured by quantifying tissue levels of ferritin using ELISA, immunofluorescence and western blot.
Expression of HFE was increased significantly in the retina of type I and type II mice models of diabetes. The downstream product hepcidin was also upregulated drastically in the retina of both mice models of diabetes. This was accompanied by significant downregulation of ferroportin in the diabetic retina. To confirm if these changes in the expression of iron regulatory proteins were associated with iron accumulation, we quantified the levels of iron storage protein, ferritin. We found a marked increase in ferritin levels by ELISA, western blot and immunofluorescence in the diabetic mice retina compared to the control retina. We also found similar changes in the expression profile of iron regulatory proteins in postmortem retina samples obtained from human diabetic patients.
Increase in retinal iron accumulation was evident in diabetic mice and human retina. Increased expression of HFE and hepcidin in diabetic retina may indicate a regulatory mechanism in response to the increase in retinal iron levels. The differential expression of iron regulatory proteins in diabetic retina is extremely novel indicating the involvement of iron in the pathogenesis of DR.
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