Purinergic dysregulation causes hypertensive glaucoma–like optic neuropathy
Youichi Shinozaki, Kenji Kashiwagi, Kazuhiko Namekata, Akiko Takeda, Nobuhiko Ohno, Bernard Robaye, Takayuki Harada, Takeshi Iwata, Schuichi Koizumi
Youichi Shinozaki, Kenji Kashiwagi, Kazuhiko Namekata, Akiko Takeda, Nobuhiko Ohno, Bernard Robaye, Takayuki Harada, Takeshi Iwata, Schuichi Koizumi
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Research Article Neuroscience Ophthalmology

Purinergic dysregulation causes hypertensive glaucoma–like optic neuropathy

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.

Authors

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

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Figure 3

Aqueous humor dynamics.

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Aqueous humor dynamics. (A) Fluorophotometry model A (Fph-A). I.p.-injec...
(A) Fluorophotometry model A (Fph-A). I.p.-injected fluorescein concentrated in the anterior chamber. (B–D) Time courses of fluorescent changes in the anterior chamber. (B) UDP and (C) timolol reduced the fluorescein influx rate, but (D) latanoprost did not (n = 10–21, **P < 0.01 vs. control, 2-way repeated ANOVA followed by Fisher’s LSD test). (E) Quantitative data for fluorescence intensity at 30 minutes (n = 10–21, *P < 0.05, **P < 0.01 vs. control, 1-way ANOVA followed by Fisher’s LSD test). (F) P2Y6KO mice showed enhanced fluorescein influx, and (G) no UDP effects were observed. (H) Quantitative data at 30 minutes of F and G (n = 10–16, *P < 0.05 vs. control, 1-way ANOVA followed by Fisher’s LSD test). (I) Representative images of latanoprost-treated eyes in the Fph-B model. Significant reduction in fluorescence intensity was observed at 30 minutes. (J) Fluorescein draining was significantly enhanced by latanoprost but not by UDP or timolol, or in P2Y6KO mice (n = 10–18, **P < 0.01 vs. control, 1-way ANOVA followed by Bonferroni correction). (K) IOP levels were significantly higher compared with those of WT mice (n = 61–318, **P < 0.01, Bonferroni correction). Data are shown as means ± SEM. Scale bars: 2 (A, inserts, and I) and 5 mm (A).