Loss of P2Y₁ receptors triggers glaucoma-like pathology in mice

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.

P2Y₁ receptor agonist was instilled into the eyes of mice, and the IOP changes were measured by a rebound-type tonometer. Expression of P2Y₁ receptors was estimated by immunohistochemistry. Ocular function was measured by a multifocal electroretinogram.

A single dose of the P2Y₁ receptor agonist transiently reduced IOP and such effects were absent in P2Y₁ receptor-deficient (P2Y₁ KO) mice. P2Y₁ receptors were functionally expressed in the ciliary body, trabecular meshwork and Schlemm's canal. Activation of P2Y₁ receptors negatively regulated aquaporin 4 (AQP4) function but up-regulated endothelial NOS (eNOS). P2Y₁ KO mice showed chronic ocular hypertension regardless of age. P2Y₁ 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.

Activation of P2Y₁ receptors reduced IOP via dual pathways including AQP4 and eNOS. Loss of P2Y₁ receptors resulted in glaucomatous optic neuropathy, suggesting that P2Y₁ receptors might provide an effective target in the treatment of glaucoma.