Xiaojuan Yang1, Raphael Rouget2, Tang Zhu2, Christiane Quiniou2,3, Shasha Lv4, Suna Jung4, Francois Duhamel2,3, Houda Tahiri5, Samy Omri5, Baraa Noueihed1, Xin Hou3, José Carlos Rivera5, Mathieu Nadeau-Vallée2, Pierre Lachapelle4, Sylvain Chemtob1,2,3,5,6,7
1Department of Pharmacology, McGill University, Montréal, QC, Canada;2Department of Pharmacology, 3Research Center CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada;4Department of Ophthalmology and Neurology-Neurosurgery, Montréal Children’s Hospital-Research Institute, McGill University, Montréal, QC, Canada;5Research Center Hôpital Maisonneuve-Rosemont, 6Department of Ophthalmology, 7Department of Pediatrics, Université de Montréal, Montréal, QC, Canada
Background: Retinal pigment epithelium (RPE) is vital for the homeostasis of the subretina including photoreceptors and choroid. Interestingly, our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE. To date, only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1. Consequently, we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81−/− mice.
Methods: GPR81−/− mice and wide type littermates were generated on a background of C57BL/6J mice. The thicknesses of their choroid were evaluated by immunohistochemistry. Meanwhile, Q-PCR, western blot and choroid sprout assay were performed. In vitro, primary retinal pigment epithelium (pRPE) cells were isolated from mice, and cultured for treatments.
Results: The thickness of choroid was reduced in GPR81−/− mice compared to GPR81+/+ mice, suggesting that GPR81 is important for the integrity of choroid. In the choroid sprout assay, lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls. For Q-PCR, most of the genes screened elevated their expression in GPR81−/− mice compared to WT mice, suggesting epigenetic modification may exist, which were confirmed by histone acetylation and HDACs activity assay.
Conclusions: Taking together, the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina. This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.
Keywords: Subretina; GPR81; epigenetic modification
