Purinergic dysregulation causes hypertensive glaucoma–like optic neuropathy

Abstract

<p class="first" id="d15451379e229">Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Although one of the highest risk factors for glaucoma is elevated intraocular pressure (IOP) and reduction in IOP is the only proven treatment, the mechanism of IOP regulation is poorly understood. We report that the P2Y ₆ receptor is critical for lowering IOP and that ablation of the P2Y ₆ gene in mice (P2Y ₆KO) results in hypertensive glaucoma–like optic neuropathy. Topically applied uridine diphosphate, an endogenous selective agonist for the P2Y ₆ receptor, decreases IOP. The P2Y ₆ receptor was expressed in nonpigmented epithelial cells of the ciliary body and controlled aqueous humor dynamics. P2Y ₆KO mice exhibited sustained elevation of IOP, age-dependent damage to the optic nerve, thinning of ganglion cell plus inner plexiform layers, and a reduction of RGC numbers. These changes in P2Y ₆KO mice were attenuated by an IOP lowering agent. Consistent with RGC damage, visual functions were impaired in middle-aged P2Y ₆KO mice. We also found that expression and function of P2Y ₆ receptors in WT mice were significantly reduced by aging, another important risk factor for glaucoma. In summary, our data show that dysfunctional purinergic signaling causes IOP dysregulation, resulting in glaucomatous optic neuropathy. </p><p class="first" id="d15451379e260">Dysfunctional purinergic signalling causes intraocular pressure dysregulation, resulting in glaucomatous optic neuropathy. </p>