The Potential Role of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) in Glaucoma: A Review

Abstract

Departmental sources Nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a regulator of many biological processes and plays an essential role in preventing oxidation, inflammation, and fibrosis. In the past 20 years, there has been increasing research on the role of Nrf2 and oxidative stress in human glaucoma, including the roles of inflammation, trabecular meshwork cells, retinal ganglion cells, Tenon's capsule, antioxidants, fibrosis, and noncoding RNAs. Studies have shown that the upregulation of Nrf2 can reduce damage from oxidative stress in the trabecular meshwork cells and the retinal ganglion cells, reduce fibrosis in Tenon's capsule fibroblasts, which may reduce the progression of fibrosis after surgery for glaucoma. The regulatory roles of Nrf2, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and exogenous compounds on trabecular meshwork cells (TMCs) and retinal ganglion cells have also been studied. The use of Nrf2 agonists, including noncoding RNAs, control the expression of Nrf2 through signaling pathways that continue to be investigated to identify effective treatments to improve clinical outcome following surgery for glaucoma. This review of publications between 1999 and 2019 aims to focus on the potential mechanisms of Nrf2 in the occurrence and development of glaucoma and the prognosis following surgical treatment. Also, several factors that induce the expression of Nrf2 in trabecular meshwork cells, retinal ganglion cells, and human Tenon's capsule fibroblasts are discussed.

Retinal oxidative stress activates the NRF2/ARE pathway: An early endogenous protective response to ocular hypertension

“…Previous studies have shown that adult Nrf2 KO mice have the same number of ganglion cells as a wild-type mouse prior to injury [ 22 , 37 , 65 ]. However, these studies did not involve an intraocular injection, nor did they assess visual function or optic nerve axons.…”

Nobiletin Alleviates Astrocyte Activation and Oxidative Stress Induced by Hypoxia In Vitro

“…Additionally, Nrf2 is thought to be the “master regulator” of antioxidant responses, regulating the expression of downstream antioxidant genes [ 44 ]. Recently, increasing evidence has demonstrated that Nrf2 is a potential therapeutic target for neurodegenerative disorders [ 44 , 45 ]. Under homeostatic conditions, Nrf2 is sequestered in the cytoplasm by binding to Kelch-like ECH associated protein 1 (Keap1).…”

The Potential of Lisosan G as a Possible Treatment for Glaucoma

“…Indeed, although IOP elevation is known as one of the most recurrent risk factors for glaucoma ( Nickells et al, 2012 ) and is the main target of pharmaceutical treatments ( Stein et al, 2021 ), often it could manifest only at late stages of the disease or may not occur, as in the case of normotensive glaucoma ( Weinreb et al, 2014 ). Similar to diabetic retinopathy, oxidative stress is likely to represent a major trigger also for glaucoma ( Domènech and Marfany, 2020 ; Garcia-Medina et al, 2020 ; Harada et al, 2020 ; Wang et al, 2020 ), and LG, which does not have any effect on the rise of IOP characteristic of D2 mice, is likely to exert its protective effect thanks to its powerful antioxidant properties.…”

“…IOP lowering is not always effective in preventing disease progression, and the form of glaucoma known as normotensive glaucoma develops with the IOP within the normal range, indicating a high degree of complexity in the pathophysiology of this retinal disease ( Weinreb et al, 2014 ). Indeed, a variety of investigations have highlighted the primary role played by oxidative stress and inflammation in the development of glaucoma ( Baudouin et al, 2020 ; Domènech and Marfany, 2020 ; Garcia-Medina et al, 2020 ; Mélik Parsadaniantz et al, 2020 ; Wang et al, 2020 ), indicating that potential treatments of this sight-threatening disease, characterized by retinal ganglion cell (RGC) degeneration and visual field loss, could be based on the use of antioxidant and/or anti-inflammatory compounds.…”