Purinergic dysregulation causes hypertensive glaucoma-like optic neuropathy.

Youichi Shinozaki,Schuichi Koizumi,Takayuki Harada,Akiko Takeda,Takeshi Iwata,Nobuhiko Ohno,Bernard Robaye,Kazuhiko Namekata,Kenji Kashiwagi

doi:10.1172/jci.insight.93456

Abstract

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 P2Y6 receptor is critical for lowering IOP and that ablation of the P2Y6 gene in mice (P2Y6KO) results in hypertensive glaucoma-like optic neuropathy. Topically applied uridine diphosphate, an endogenous selective agonist for the P2Y6 receptor, decreases IOP. The P2Y6 receptor was expressed in nonpigmented epithelial cells of the ciliary body and controlled aqueous humor dynamics. P2Y6KO 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 P2Y6KO mice were attenuated by an IOP lowering agent. Consistent with RGC damage, visual functions were impaired in middle-aged P2Y6KO mice. We also found that expression and function of P2Y6 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.

Highlights

Glaucoma is the second most common cause of blindness and affects more than 70 million people worldwide [1, 2]
We report that the P2Y6 receptor is essential for regulating the intraocular pressure (IOP), and deficiency of this gene causes elevated IOP and hypertensive glaucoma–like phenotypes, including degeneration of the optic nerve and retinal ganglion cells (RGCs) and dysregulated visual functions
Regarding the mechanism involved in IOP reduction, the P2Y6 receptor in the NPE cells suppressed the production of aqueous humor from the ciliary body (CB)

Summary

Introduction

Glaucoma is the second most common cause of blindness and affects more than 70 million people worldwide [1, 2]. ATP and nucleotides are present in the aqueous humor [5]. Nucleotides are released from various tissues and cells, including lens [6], trabecular meshwork [7], whole retina [8], corneal endothelial cells [9], retinal ganglion cells (RGCs) [10], retinal astrocytes [11], and ciliary body (CB) [12]. Extracellular nucleotides including ATP bind to purinergic P2 receptors [15]. P2Y4 and P2Y6 receptors are present in cornea, ciliary processes, photoreceptors, and ganglion cells. P2Y11 receptor is expressed in the retinal pigmented epithelium. We report that the P2Y6 receptor is responsible for IOP reduction and that its dysfunction causes hypertensive glaucoma–like optic neuropathy

Methods

Results

Conclusion