Circadian Regulation of IOP Rhythm by Dual Pathways of Glucocorticoids and the Sympathetic Nervous System
Circadian Regulation of IOP Rhythm by Dual Pathways of Glucocorticoids and the Sympathetic Nervous System
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DOI：
10.1167/iovs.61.3.26
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发表时间：
2020-03-01
影响因子：
4.4
通讯作者：
Masubuchi, Satoru
中科院分区：
文献类型：
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作者：
Ikegami, Keisuke;Shigeyoshi, Yasufumi;Masubuchi, Satoru
目的。眼压升高可引起青光眼。眼内压的昼夜节律取决于房水的动态，并与昼夜节律起搏器（即视交叉上核）同步。视交叉上核通过交感神经或肾上腺糖皮质激素重置外周时钟。然而，IOP节律的详细机制尚不清楚。本研究的目的是验证这一调控途径。C57BL/6J小鼠行肾上腺切除术和/或颈上神经节切除术。在光/暗循环和持续黑暗条件下测量他们的眼内压节律。眼内给予皮质酮或去甲肾上腺素。免疫组织化学分析肾上腺素能受体、糖皮质激素受体和时钟蛋白Bmal1和Per1的定位。对肾上腺切除和/或颈上神经节切除小鼠培养虹膜/睫状体荧光素酶节律进行监测，以评估手术对局部时钟的影响。测定视网膜和睫状体上皮特异性Bmal1基因敲除小鼠的IOP节律，以确定局部时钟的意义。肾上腺切除术和颈上神经节切除术破坏了虹膜/睫状体培养物的IOP节律和生物钟。注入皮质酮和去甲肾上腺素可恢复IOP节律。β 2-肾上腺素能受体、糖皮质激素受体和时钟蛋白在纤毛体的非色素上皮内强烈表达。然而，组织特异性Bmal1敲除小鼠维持其IOP节律。这些发现表明视交叉上核通过皮质酮和去甲肾上腺素双通路直接驱动眼压节律，而不是睫状体时钟，这可能对青光眼的时间治疗有用。
PURPOSE. Elevated IOP can cause the development of glaucoma. The circadian rhythm of IOP depends on the dynamics of the aqueous humor and is synchronized with the circadian rhythm pacemaker, that is, the suprachiasmatic nucleus. The suprachiasmatic nucleus resets peripheral clocks via sympathetic nerves or adrenal glucocorticoids. However, the detailed mechanisms underlying IOP rhythmicity remain unclear. The purpose of this study was to verify this regulatory pathway.METHODS. Adrenalectomy and/or superior cervical ganglionectomy were performed in C57BL/6J mice. Their IOP rhythms were measured under light/dark cycle and constant dark conditions. Ocular administration of corticosterone or norepinephrine was also performed. Localization of adrenergic receptors, glucocorticoid receptors, and clock proteins Bmal1 and Per1 were analyzed using immunohistochemistry. Period2::luciferase rhythms in the cultured iris/ciliary bodies of adrenalectomized and/or superior cervical ganglionectomized mice were monitored to evaluate the effect of the procedures on the local clock. The IOP rhythm of retina and ciliary epithelium-specific Bmal1 knockout mice were measured to determine the significance of the local clock.RESULTS. Adrenalectomy and superior cervical ganglionectomy disrupted IOP rhythms and the circadian clock in the iris/ciliary body cultures. Instillation of corticosterone and norepinephrine restored the IOP rhythm. beta 2-Adrenergic receptors, glucocorticoid receptors, and clock proteins were strongly expressed within the nonpigmented epithelia of the ciliary body. However, tissue-specific Bmal1 knock-out mice maintained their IOP rhythm.CONCLUSIONS. These findings suggest direct driving of the IOP rhythm by the suprachiasmatic nucleus, via the dual corticosterone and norepinephrine pathway, but not the ciliary clock, which may be useful for chronotherapy of glaucoma.