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Masamitsu Shimazawa, Mayu Moriguchi, Shinsuke Nakamura, Hideaki Hara; The involvement of G protein-coupled receptor 35 on pathology of non-exudative age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5386.
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The retinal pigment epithelium (RPE) is a highly specialized epithelial cell that interacts with photoreceptors and the choriocapillaris. The RPE degeneration, caused by aging and the accumulation of environmental stresses, plays a pivotal role in pathology of non-exudative age-related macular degeneration (AMD), and the leading cause of blindness in the elderly. Nevertheless, the detail information on the mechanisms of the RPE degeneration is poorly understood and there is no pharmacotherapy targeting RPE protection. The purpose of this study was discovery of therapeutic targets on RPE degeneration using sodium iodate (NaIO3)-induced RPE degeneration model in mice.
NaIO3 was dissolved in phosphate-buffered saline (PBS), and 8 week-old male C57BL/6J mice were injected with 20 or 40 mg/kg of NaIO3 through a tail vein under anesthesia. Seven days after NaIO3 administration, the eyes were enucleated and RPE-eyecup complexes were isolated for gene expression microarray analysis. The results of the analysis were compared with the gene expression profile of non-exudative AMD patients form National Center for Biotechnology Information (NICB) database. The genes whose expression level increased more than twice as compared with the control in both the result of microarray and NICB database were selected. The expression level of G protein-coupled receptor 35 (Gpr35) after NaIO3 administration was assessed by immunostaining and reverse transcription polymerase chain reaction. The effect of cromolyn, a non-selective Gpr35 agonist, against NaIO3-induced ARPE-19 cell damage was evaluated by cell viability assay.
In RPE-choroid complexes of both NaIO3 administrated mice and non-exudative AMD patients, the gene expression level of Gpr35 significantly increased compared with that of control. In particular, the upregulation of Gpr35 gene in RPE-choroid complexes of 40 mg/kg, i.v. NaIO3 administrated mice continued from 3 day after NaIO3 injection. In immunostaining, the expression level of Gpr35 protein was increased in subretinal area of NaIO3 administrated mice. Furthermore, cromolyn treatment reduced NaIO3-induced ARPE-19 cell death.
These findings indicate that the upregulation of Gpr35 is involved in AMD pathogenesis. Gpr35 might be one of the potential therapeutic targets for non-exudative AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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