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Vadivel Ganapathy, Paresh Chothe, Jaya P. Gnana-Prakasam, Ram Kannan, David R. Hinton, Sylvia B. Smith, Pamela M. Martin; Transport Of Hepcidin, An Iron-regulatory Peptide Hormone, Into Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3333.
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RPE expresses two transport systems (SOPT1 and SOPT2) for oligopeptides. To date, the only endogenous peptides that have been identified as substrates for SOPT1 and SOPT2 are opioid peptides. Hepcidin is an iron-regulatory peptide hormone consisting of 25 amino acids. It is produced by several cell types in retina. This hormone binds to ferroportin, an iron exporter on cell surface, and facilitates its degradation. Here we investigated if hepcidin is a substrate for SOPT1 and SOPT2 and if the hormone has any intracellular function in RPE.
Interaction of hepcidin with SOPT1 and SOPT2 was studied by monitoring the effect of hepcidin on the transport of deltorphin II (a substrate for SOPT1) and DADLE (a substrate for SOPT2) in RPE (ARPE-19, HRPE, primary mouse and human RPE). Entry of hepcidin into RPE was studied directly by epiflurescence and flow cytometry using FITC-labeled hepcidin. Intracellular actions of hepcidin in RPE were investigated by examining its effect on ferroportin mRNA expression.
Hepcidin inhibited competitively the uptake of deltorphin II and DADLE with IC50 values in the range of 0.4 - 1.7 microM in different RPE cells. FITC-hepcidin was taken up into RPE, and this uptake was inhibited by deltorphin II and DADLE. The entry of the fluorescent hepcidin into cells was confirmed by flow cytometry. The uptake process was Na-dependent and inhibitable by deltorphin II and DADLE. Incubation of RPE with hepcidin decreased the expression of ferroportin mRNA. This effect was not a consequence of hepcidin-induced ferroportin degradation because excessive iron accumulation in RPE, which is expected to occur in these cells as a result of ferroportin degradation, increased the levels of ferroportin mRNA.
Hepcidin is taken up into RPE via specific transport systems. Once inside the cells, this hormone decreases the expression of ferroportin. This study reveals a novel intracellular function for hepcidin other than its established cell surface action on ferroportin.
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