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J. Gnana Prakasam, S. Ananth, P. M. Martin, S. B. Smith, V. Ganapathy; Expression of Succinate Receptor Gpr91 in Retinal Pigment Epithelium (RPE) in Control and Hfe Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):501.
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GPR91 is a G-protein-coupled receptor for succinate. It plays an important role in the production of vascular endothelial growth factor (VEGF); it is also a potent mediator of vascular growth in normal retina and in diseases associated with proliferative retinopathy. RPE-derived VEGF is important for maintenance of choriocapillaris and plays a pathogenic role in age-related macular degeneration (AMD). However, nothing is known on GPR91 expression in RPE. Excessive iron accumulation is a hallmark of AMD retinas and is also seen in patients with hemochromatosis. Here we examined the expression GPR91 in RPE in normal mice and in a mouse model of hemochromatosis.
Expression and distribution of GPR91 in mouse retina was determined by RT-PCR and confocal immunofluorescence. Bioluminescence Resonance Energy Transfer (BRET) assay was done to confirm that succinate is a ligand for GPR91. Hfe-/- mice were used as an animal model for hemochromatosis. The influence of excessive iron on expression of GPR91 in RPE was analyzed in vitro by exposing RPE cell lines and primary cells to ferric ammonium citrate (FAC).
GPR91 mRNA and protein are expressed in RPE as well as in neural retina. The expression is restricted to the apical membrane in RPE. Succinate functions as a ligand for GPR91 based on BRET assay. Expression of GPR91 is markedly higher in Hfe-/- mice throughout the retina including RPE. Primary RPE cells from Hfe-/- mice also show increased expression of GPR91 compared to control RPE cells. RPE cell lines and primary RPE cells treated with FAC show increased expression of GPR91 similar to Hfe-/- mice.
RPE expresses GPR91. Localization of GPR91 in the apical membrane of RPE suggests that succinate in the subretinal space plays a role in the activation of GPR91. Increased GPR91 expression in RPE and in retina during iron overload indicates that excessive iron accumulation in retina as seen in patients with AMD and hemochromatosis might play a pathologic role in neovasculatization through increased GPR91-mediated VEGF secretion.
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