PDF(Pubmed)
Abstract：
Ocular hypertension (OHT) caused by mechanical stress and chronic glucocorticoid exposure reduces the hydraulic permeability of the conventional outflow pathway. It increases the risk for irreversible vision loss, yet healthy individuals experience nightly intraocular pressure (IOP) elevations without adverse lifetime effects. It is not known which pressure sensors regulate physiological vs. pathological OHT nor how they impact the permeability of the principal drainage pathway through the trabecular meshwork (TM). We report that OHT induced by the circadian rhythm, occlusion of the iridocorneal angle and glucocorticoids requires activation of TRPV4, a stretch-activated cation channel. Wild-type mice responded to nocturnal topical administration of the agonist GSK1016790A with IOP lowering, while intracameral injection of the agonist elevated diurnal IOP. Microinjection of TRPV4 antagonists HC067047 and GSK2193874 lowered IOP during the nocturnal OHT phase and in hypertensive eyes treated with steroids or injection of polystyrene microbeads. Conventional outflow-specific Trpv4 knockdown induced partial IOP lowering in mice with occluded iridocorneal angle and protected retinal neurons from pressure injury. Indicating a central role for TRPV4-dependent mechanosensing in trabecular outflow, HC067047 doubled the outflow facility in TM-populated steroid-treated 3D nanoscaffolds. Tonic TRPV4 signaling thus represents a fundamental property of TM biology as a driver of increased in vitro and in vivo outflow resistance. The TRPV4-dependence of OHT under conditions that mimic primary and secondary glaucomas could be explored as a novel target for glaucoma treatments.
摘要：
由机械应力和慢性糖皮质激素暴露引起的眼部高血压（OHT）降低了常规流出途径的水力渗透性。它增加了不可逆转的视力丧失的风险，然而,健康个体会经历夜间眼内压(IOP)升高,而无不良终生影响.目前还不知道哪些压力传感器调节生理与病理性OHT以及它们如何影响通过小梁网（TM）的主要引流途径的渗透性。我们报道了由昼夜节律引起的OHT，虹膜角膜角和糖皮质激素的闭塞需要激活TRPV4，这是一种拉伸激活的阳离子通道。野生型小鼠对激动剂GSK1016790A的夜间局部给药具有降低IOP的反应，而前房内注射激动剂会升高昼夜眼压。TRPV4拮抗剂HC067047和GSK2193874的显微注射在夜间OHT阶段和用类固醇或注射聚苯乙烯微珠治疗的高血压眼中降低了IOP。常规的流出特异性Trpv4敲低可在虹膜角膜角闭塞的小鼠中诱导部分IOP降低，并保护视网膜神经元免受压力损伤。表明TRPV4依赖性机械传感在小梁流出中的核心作用，HC067047使TM填充的类固醇处理的3D纳米支架中的流出设施增加了一倍。因此,TonicTRPV4信号传导代表TM生物学的基本特性,作为增加的体外和体内流出阻力的驱动因素。在模拟原发性和继发性青光眼的条件下，OHT的TRPV4依赖性可以作为青光眼治疗的新目标进行探索。
