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V. Ganapathy, J. GnanaPrakasam, S. S. Atherton, S. B. Smith; Expression of Iron-regulatory Protein Hemojuvelin in Retina and Its Regulation by Cytomegalovirus. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3417.
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© ARVO (1962-2015); The Authors (2016-present)
Hemochromatosis (HH) is a genetic disorder of iron overload. HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin (Hjv) represent five iron-regulatory proteins whose loss-of-function mutations cause HH. Expression of first four genes in retina has been established. Present studies were carried out to determine whether Hjv is expressed in retina. Infection of mammalian cells with cytomegalovirus (CMV) leads to changes in iron homeostasis. Since CMV retinitis is a leading cause of blindness, we also studied the regulation of expression of HJV and other iron-regulatory proteins in retina during CMV infection.
RT-PCR was used to assess gene expression. To localize Hjv mRNA and protein, in situ hybridization and immunofluorescence methods were used. Ocular inoculation of murine CMV was done by injection of the virus (or PBS for control) into the left eye of mice by the supraciliary route.
RT-PCR showed expression of Hjv in RPE/eyecup and neural retina. In situ hybridization and immunohistochemistry confirmed the presence of Hjv mRNA and protein in RPE, outer nuclear layer, inner nuclear layer, and ganglion cell layer. In RPE, Hjv expression was restricted to apical membrane. Infection of primary cultures of mouse RPE with CMV increased Hjv mRNA and protein levels. Under similar conditions, Hfe mRNA levels were not altered, but Hfe protein levels were reduced. In contrast, there was no change in hepcidin expression. These findings were confirmed in vivo with infection of mouse retina with CMV. The CMV-induced upregulation of Hjv expression in RPE was independent of changes that occurred in Hfe because it was also seen in Hfe-null RPE cells.
Hjv is expressed in RPE, ONL, INL and GCL of mouse retina. The expression of HJV and HFE in RPE is polarized, the former in the apical membrane and the latter in the basolateral membrane. We predict an essential role for HJV in retinal iron homeostasis. The observed changes in the expression of HJV, independent of HFE, during CMV infection in retina may have significance in the pathophysiology of CMV retinitis.
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