Elucidating glial responses to products of diabetes-associated systemic dyshomeostasis

• Published in: Progress in retinal and eye research 2023-05, Vol.94, p.101151-101151, Article 101151
• Main Authors: Padovani-Claudio, Dolly Ann, Ramos, Carla J., Capozzi, Megan E., Penn, John S.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiotensin II - therapeutic use; Diabetes Mellitus; Diabetic Retinopathy; Dysregulation; Glucose; Homeostasis; Humans; Hyperglycemia; Hyperlipidemia; Hypertension; Inflammation; Neuroglia - pathology; Palmitic Acid - therapeutic use; Retinal glia; Visual impairment
• ISSN: 1350-9462; 1873-1635
• DOI: 10.1016/j.preteyeres.2022.101151

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 activati