Loss of P2Y1 receptors triggers glaucoma-like pathology in mice

Background and Purpose Glaucoma, the leading cause of blindness, damages the retinal ganglion cells. Elevated intraocular pressure (IOP) is a high-risk factor for glaucoma, so topical hypotensive drugs are usually used for treatment. Because not all patients do not respond adequately to current treatments, there is a need to identify a new molecular target to reduce IOP. Here, we have assessed the role of P2Y1 receptors in mediating elevated IOP. Experimental Approach P2Y(1) receptor agonist was instilled into the eyes of mice, and the IOP changes were measured by a rebound-type tonometer. Expression of P2Y(1) receptors was estimated by immunohistochemistry. Ocular function was measured by a multifocal electroretinogram. Key Results A single dose of the P2Y(1) receptor agonist transiently reduced IOP and such effects were absent in P2Y(1) receptor-deficient (P2Y(1)KO) mice. P2Y(1) receptors were functionally expressed in the ciliary body, trabecular meshwork and Schlemm's canal. Activation of P2Y(1) receptors negatively regulated aquaporin 4 (AQP4) function but up-regulated endothelial NOS (eNOS). P2Y(1)KO mice showed chronic ocular hypertension regardless of age. P2Y(1)KO mice at 3 months old showed no damage to retinal ganglion cells, whereas 12-month-old mice showed a significant loss of these cells and impairment of ocular functions. Damage to retinal ganglion cells was attenuated by chronic administration of an IOP-reducing agent. Conclusion and Implications Activation of P2Y(1) receptors reduced IOP via dual pathways including AQP4 and eNOS. Loss of P2Y(1) receptors resulted in glaucomatous optic neuropathy, suggesting that P2Y(1) receptors might provide an effective target in the treatment of glaucoma.

Automated summary

Activation of P2Y(1) receptors can reduce intraocular pressure through dual pathways involving AQP4 and eNOS, while loss of P2Y(1) receptors leads to glaucomatous optic neuropathy. Chronic administration of an IOP-reducing agent can attenuate damage to retinal ganglion cells.