Loss of P2Y1 receptors triggers glaucoma-like pathology in mice

Background and purpose Glaucoma, the leading cause of blindness, damages the retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a high-risk factor for glaucoma, so topical hypotensive drugs are usually used for treatment. However, not all patients adequately respond to current treatments, so there is a need to identify a new molecular target to reduce IOP. This study was aimed to determine whether the P2Y1 receptors reduce IOP. Experimental approach P2Y1 receptor agonist was instilled on the eyes of mice, and the IOP changes were measured by a rebound-type tonometer. Expression of P2Y1 receptors was estimated by immunohistochemistry. The ocular function was measured by a multifocal electroretinogram. Key results Single-dose of the P2Y1 receptor agonist transiently reduced IOP. The hypotensive effect was disappeared in P2Y1 receptor-deficient (P2Y1 KO) mice. The P2Y1 receptor was functionally expressed in the ciliary body, trabecular meshwork, and Schlemm's canal. We found that P2Y1 receptor negatively regulated aquaporin 4 (AQP4) whereas positively regulated endothelial nitric oxide synthase (eNOS). P2Y1 KO mice showed chronic ocular hypertension regardless of their ages. The P2Y1 KO mice at 3 months old showed no RGC damage, whereas 12-month-old mice showed a significant loss of RGCs and impairment of ocular functions. The RGC damages were attenuated by chronic administration of an IOP-reducing agent. Conclusions and implications P2Y1 receptor activation reduces IOP via dual pathways including AQP4 and eNOS. Dysregulated P2Y1 receptors results in glaucomatous optic neuropathy, suggesting that P2Y1 receptor might be an attractive target for the treatment of glaucoma.