The Intertwined Roles of Oxidative Stress and Endoplasmic Reticulum Stress in Glaucoma

Overview

Journal Antioxidants (Basel)

Date 2022 May 28

PMID 35624748

Authors

Daire John Hurley

Caoimhe Normile

Mustapha Irnaten

Colm OBrien

Affiliations

Soon will be listed here.

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicated in the pathogenesis of many diseases. Oxidative stress occurs when there is an imbalance in redox homeostasis, with reactive oxygen species producing processes overcoming anti-oxidant defensive processes. Oxidative stress works in a synergistic fashion with endoplasmic reticulum stress, to drive glaucomatous damage to trabecular meshwork, retinal ganglion cells and the optic nerve head. We discuss the oxidative stress and endoplasmic reticulum stress pathways and their connections including their key intermediary, calcium. We highlight therapeutic options aimed at disrupting these pathways and discuss their potential role in glaucoma treatment.

Citing Articles

The molecular mechanisms underlying retinal ganglion cell apoptosis and optic nerve regeneration in glaucoma (Review).

Wang X, Sun L, Han X, Li Z, Xing Y, Chen X Int J Mol Med. 2025; 55(4).

PMID: 39950327 PMC: 11878485. DOI: 10.3892/ijmm.2025.5504.

Glaucoma and dietary links: insights from high-salt intake, the Mediterranean diet, and specific nutrients.

Yang Y, Zhou H, Hong Z Front Nutr. 2024; 11:1461748.

PMID: 39512517 PMC: 11541052. DOI: 10.3389/fnut.2024.1461748.

Gene therapy for glaucoma: Targeting key mechanisms.

Henderson J, OCallaghan J, Campbell M Vision Res. 2024; 225:108502.

PMID: 39423611 PMC: 11579448. DOI: 10.1016/j.visres.2024.108502.

Ocular Inflammation and Oxidative Stress as a Result of Chronic Intermittent Hypoxia: A Rat Model of Sleep Apnea.

Donkor N, Gardner J, Bradshaw J, Cunningham R, Inman D Antioxidants (Basel). 2024; 13(7).

PMID: 39061946 PMC: 11273423. DOI: 10.3390/antiox13070878.

Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review.

Golmohammadi M, Meibodi S, Al-Hawary S, Gupta J, Sapaev I, Najm M Animal Model Exp Med. 2024; 7(3):195-207.

PMID: 38808561 PMC: 11228121. DOI: 10.1002/ame2.12438.

References

Maddineni P, Kasetti R, Kodati B, Yacoub S, Zode G . Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9. Int J Mol Sci. 2021; 22(18). PMC: 8465971. DOI: 10.3390/ijms221810095. View

Zukerman R, Harris A, Oddone F, Siesky B, Verticchio Vercellin A, Ciulla T . Glaucoma Heritability: Molecular Mechanisms of Disease. Genes (Basel). 2021; 12(8). PMC: 8391305. DOI: 10.3390/genes12081135. View

Wang Q, Zheng Q, Tan H, Zhang B, Li X, Yang Y . TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel. Cell. 2016; 165(6):1454-1466. DOI: 10.1016/j.cell.2016.04.051. View

Li S, Lo A . Lutein protects RGC-5 cells against hypoxia and oxidative stress. Int J Mol Sci. 2010; 11(5):2109-17. PMC: 2885097. DOI: 10.3390/ijms11052109. View

Cao S, Kaufman R . Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal. 2014; 21(3):396-413. PMC: 4076992. DOI: 10.1089/ars.2014.5851. View

Coelho D, Domingos P . Physiological roles of regulated Ire1 dependent decay. Front Genet. 2014; 5:76. PMC: 3997004. DOI: 10.3389/fgene.2014.00076. View

Athanasiou D, Aguila M, Bellingham J, Kanuga N, Adamson P, Cheetham M . The role of the ER stress-response protein PERK in rhodopsin retinitis pigmentosa. Hum Mol Genet. 2017; 26(24):4896-4905. PMC: 5868081. DOI: 10.1093/hmg/ddx370. View

Rokicki W, Zalejska-Fiolka J, Pojda-Wilczek D, Hampel A, Majewski W, Ogultekin S . Differences in serum oxidative status between glaucomatous and nonglaucomatous cataract patients. BMC Ophthalmol. 2017; 17(1):13. PMC: 5311834. DOI: 10.1186/s12886-017-0409-3. View

Zhao R, Jiang S, Zhang L, Yu Z . Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int J Mol Med. 2019; 44(1):3-15. PMC: 6559295. DOI: 10.3892/ijmm.2019.4188. View

10.

Cicik E, Tekin H, Akar S, Ekmekci O, Donma O, Koldas L . Interleukin-8, nitric oxide and glutathione status in proliferative vitreoretinopathy and proliferative diabetic retinopathy. Ophthalmic Res. 2003; 35(5):251-5. DOI: 10.1159/000072145. View

11.

Thomas C, Berry M, Logan A, Blanch R, Ahmed Z . Caspases in retinal ganglion cell death and axon regeneration. Cell Death Discov. 2018; 3:17032. PMC: 5903394. DOI: 10.1038/cddiscovery.2017.32. View

12.

Boyce M, Bryant K, Jousse C, Long K, Harding H, Scheuner D . A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005; 307(5711):935-9. DOI: 10.1126/science.1101902. View

13.

Rozpedek-Kaminska W, Wojtczak R, Szaflik J, Szaflik J, Majsterek I . The Genetic and Endoplasmic Reticulum-Mediated Molecular Mechanisms of Primary Open-Angle Glaucoma. Int J Mol Sci. 2020; 21(11). PMC: 7312987. DOI: 10.3390/ijms21114171. View

14.

Feilchenfeld Z, Yucel Y, Gupta N . Oxidative injury to blood vessels and glia of the pre-laminar optic nerve head in human glaucoma. Exp Eye Res. 2008; 87(5):409-14. DOI: 10.1016/j.exer.2008.07.011. View

15.

Ledford H, Callaway E . Pioneers of revolutionary CRISPR gene editing win chemistry Nobel. Nature. 2020; 586(7829):346-347. DOI: 10.1038/d41586-020-02765-9. View

16.

Muenster S, Lieb W, Fabry G, Allen K, Kamat S, Guy A . The Ability of Nitric Oxide to Lower Intraocular Pressure Is Dependent on Guanylyl Cyclase. Invest Ophthalmol Vis Sci. 2017; 58(11):4826-4835. PMC: 5624778. DOI: 10.1167/iovs.17-22168. View

17.

Calderon G, Juarez O, Hernandez G, Punzo S, De la Cruz Z . Oxidative stress and diabetic retinopathy: development and treatment. Eye (Lond). 2017; 31(8):1122-1130. PMC: 5558229. DOI: 10.1038/eye.2017.64. View

18.

Lin H, Stein J, Nan B, Childers D, Newman-Casey P, Thompson D . Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus. JAMA Ophthalmol. 2015; 133(8):915-23. PMC: 4537372. DOI: 10.1001/jamaophthalmol.2015.1440. View

19.

Wiggs J . Glaucoma Genes and Mechanisms. Prog Mol Biol Transl Sci. 2015; 134:315-42. PMC: 6663557. DOI: 10.1016/bs.pmbts.2015.04.008. View

20.

Zeitz O, Wagenfeld L, Wirtz N, Galambos P, Matthiesen N, Wiermann A . Influence of oxygen free radicals on the tone of ciliary arteries: a model of vasospasms of ocular vasculature. Graefes Arch Clin Exp Ophthalmol. 2007; 245(9):1327-33. DOI: 10.1007/s00417-006-0526-9. View