Upregulation of the endothelin A (ET(A)) receptor and its association with neurodegeneration in a rodent model of glaucoma.
Upregulation of the endothelin A (ET(A)) receptor and its association with neurodegeneration in a rodent model of glaucoma.
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DOI：
10.1186/s12868-017-0346-3
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发表时间：
2017-03-01
期刊：
影响因子：
2.4
通讯作者：
Krishnamoorthy RR
中科院分区：
文献类型：
--
作者：
McGrady NR;Minton AZ;Stankowska DL;He S;Jefferies HB;Krishnamoorthy RR
原发性开角型青光眼是一组异质性的视神经病变，其导致视神经变性和视网膜神经节细胞（RGC）的损失，如果任其发展，最终导致失明。眼内压（IOP）升高是发展为青光眼的最主要危险因素，降低IOP是目前唯一可用的治疗方法。然而，尽管降低了IOP，但在一些患者中神经退行性作用持续存在。因此，除了IOP降低疗法之外，开发促进RGC的神经保护的方法将是有益的。内皮素系统是针对脑昏迷性神经变性进行干预的关键靶点。内皮素家族的肽和受体，特别是内皮素-1（ET-1）和内皮素B（ET B）受体，已显示在青光眼中具有神经变性作用。本研究的目的是研究内皮素A（ETA）受体蛋白表达的变化在成年雄性布朗挪威大鼠的眼压升高后的莫里森的高眼压模型和影响的ETA受体过表达RGC活力在体外。通过巩膜外静脉注射高渗盐水，在Brown Norway大鼠的一只眼睛中进行IOP升高。在IOP升高2周后，大鼠眼视网膜切片的免疫组织化学分析显示，在视网膜多个层（包括内丛状层、神经节细胞层和外丛状层）中ETA受体的免疫染色呈增加趋势。4周后，眼压升高，ETA受体表达的免疫染色显着增加，发现在视网膜中，主要是在内部网状层和神经节细胞。在眼压升高的大鼠视网膜的外网状层中也发现了ETA受体染色的适度增加。细胞培养研究表明，与空载体转染的细胞相比，661 W细胞以及原代RGC中ETA受体的过表达降低了细胞活力。腺相关病毒介导的ETA受体的过表达在原发性RGCs中产生ETB受体的增加。升高的IOP导致视网膜中ETA受体表达的明显变化。ETA受体的过表达导致细胞活力的总体降低，伴随着ETB受体水平的增加，这表明ETA和ETB受体都参与介导细胞死亡。这些发现提高了ETA/ETB双受体拮抗剂作为神经保护治疗昏迷性神经病变的发展的可能性。本文的在线版本（doi：10.1186/s12868-017-0346-3）包含补充材料，可供授权用户使用。
Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison’s model of ocular hypertension and the impact of ETA receptor overexpression on RGC viability in vitro. IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETA receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs. Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy. The online version of this article (doi:10.1186/s12868-017-0346-3) contains supplementary material, which is available to authorized users.