In:
British Journal of Pharmacology, Wiley, Vol. 178, No. 22 ( 2021-11), p. 4552-4571
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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