Elucidating glial responses to products of diabetes-associated systemic dyshomeostasis

IF 18.6 1区 医学 Q1 OPHTHALMOLOGY Progress in Retinal and Eye Research Pub Date : 2023-05-01 DOI:10.1016/j.preteyeres.2022.101151
Dolly Ann Padovani-Claudio , Carla J. Ramos , Megan E. Capozzi , John S. Penn
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Abstract

Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. DR has non-proliferative stages, characterized in part by retinal neuroinflammation and ischemia, and proliferative stages, characterized by retinal angiogenesis. Several systemic factors, including poor glycemic control, hypertension, and hyperlipidemia, increase the risk of DR progression to vision-threatening stages. Identification of cellular or molecular targets in early DR events could allow more prompt interventions pre-empting DR progression to vision-threatening stages.

Glia mediate homeostasis and repair. They contribute to immune surveillance and defense, cytokine and growth factor production and secretion, ion and neurotransmitter balance, neuroprotection, and, potentially, regeneration. Therefore, it is likely that glia orchestrate events throughout the development and progression of retinopathy. Understanding glial responses to products of diabetes-associated systemic dyshomeostasis may reveal novel insights into the pathophysiology of DR and guide the development of novel therapies for this potentially blinding condition.

In this article, first, we review normal glial functions and their putative roles in the development of DR. We then describe glial transcriptome alterations in response to systemic circulating factors that are upregulated in patients with diabetes and diabetes-related comorbidities; namely glucose in hyperglycemia, angiotensin II in hypertension, and the free fatty acid palmitic acid in hyperlipidemia. Finally, we discuss potential benefits and challenges associated with studying glia as targets of DR therapeutic interventions.

In vitro stimulation of glia with glucose, angiotensin II and palmitic acid suggests that: 1) astrocytes may be more responsive than other glia to these products of systemic dyshomeostasis; 2) the effects of hyperglycemia on glia are likely to be largely osmotic; 3) fatty acid accumulation may compound DR pathophysiology by promoting predominantly proinflammatory and proangiogenic transcriptional alterations of macro and microglia; and 4) cell-targeted therapies may offer safer and more effective avenues for DR treatment as they may circumvent the complication of pleiotropism in retinal cell responses.

Although several molecules previously implicated in DR pathophysiology are validated in this review, some less explored molecules emerge as potential therapeutic targets. Whereas much is known regarding glial cell activation, future studies characterizing the role of glia in DR and how their activation is regulated and sustained (independently or as part of retinal cell networks) may help elucidate mechanisms of DR pathogenesis and identify novel drug targets for this blinding disease.

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阐明胶质细胞对糖尿病相关全身失衡产物的反应
糖尿病视网膜病变(DR)是导致工作年龄成年人失明的主要原因。DR有非增殖期,部分以视网膜神经炎症和缺血为特征,还有增殖期,以视网膜血管生成为特征。一些系统性因素,包括血糖控制不佳、高血压和高脂血症,会增加DR发展到视力威胁阶段的风险。在早期DR事件中识别细胞或分子靶点可以使更及时的干预措施提前预防DR进展到视力威胁阶段。胶质细胞介导体内平衡和修复。它们有助于免疫监测和防御、细胞因子和生长因子的产生和分泌、离子和神经递质的平衡、神经保护,以及潜在的再生。因此,神经胶质细胞很可能在视网膜病变的整个发展和进展过程中协调事件。了解神经胶质细胞对糖尿病相关系统性稳态失调产物的反应,可能会揭示DR病理生理学的新见解,并指导开发这种潜在致盲性疾病的新疗法。在这篇文章中,首先,我们回顾了正常的神经胶质功能及其在DR发展中的假定作用。然后,我们描述了在糖尿病和糖尿病相关合并症患者中,神经胶质转录组对系统循环因子上调的反应;即高血糖中的葡萄糖、高血压中的血管紧张素II和高脂血症中的游离脂肪酸棕榈酸。最后,我们讨论了研究神经胶质细胞作为DR治疗干预靶点的潜在益处和挑战。葡萄糖、血管紧张素II和棕榈酸对胶质细胞的体外刺激表明:1)星形胶质细胞可能比其他胶质细胞对这些系统稳态失调的产物更敏感;2) 高血糖对胶质细胞的影响可能主要是渗透性的;3) 脂肪酸积累可能通过促进大胶质细胞和小胶质细胞的主要促炎和促血管生成转录改变来复合DR的病理生理学;和4)细胞靶向治疗可以为DR治疗提供更安全、更有效的途径,因为它们可以避免视网膜细胞反应中多效性的并发症。尽管先前与DR病理生理学有关的几种分子在本综述中得到了验证,但一些探索较少的分子成为潜在的治疗靶点。尽管对神经胶质细胞激活有很多了解,但未来研究神经胶质在DR中的作用以及它们的激活是如何被调节和维持的(独立地或作为视网膜细胞网络的一部分)可能有助于阐明DR的发病机制,并确定这种致盲疾病的新药物靶点。
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来源期刊
CiteScore
34.10
自引率
5.10%
发文量
78
期刊介绍: Progress in Retinal and Eye Research is a Reviews-only journal. By invitation, leading experts write on basic and clinical aspects of the eye in a style appealing to molecular biologists, neuroscientists and physiologists, as well as to vision researchers and ophthalmologists. The journal covers all aspects of eye research, including topics pertaining to the retina and pigment epithelial layer, cornea, tears, lacrimal glands, aqueous humour, iris, ciliary body, trabeculum, lens, vitreous humour and diseases such as dry-eye, inflammation, keratoconus, corneal dystrophy, glaucoma and cataract.
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