Nutrigenetic reprogramming of oxidative stress

Abstract

Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the complex mechanisms underlying these processes. In the photoreceptors, we highlight that Nrf2 preserves their survival and function by maintaining oxidation homeostasis. In the retinal pigment epithelium, Nrf2 similarly plays a critical role in oxidative stabilization but also maintains mitochondrial motility and autophagy-related lipid metabolic processes. In endothelial cells, Nrf2 seems to promote proper vascularization and revascularization through concurrent activation of antioxidative and angiogenic factors as well as inhibition of inflammatory cytokines. Finally, Nrf2 protects retinal ganglion cells against apoptotic cell death. Importantly, we show that Nrf2-mediated protection of the various retinal tissues corresponds to a preservation of functional vision. Altogether, this review underscores the potential of the Nrf2-Keap1 pathway as a powerful tool against retinal degeneration. Key insights into this elegant oxidative defense mechanism may ultimately pave the path toward a universal therapy for various inherited and environmental retinal disorders.

Keywords: Antioxidants; oxidative stress; retinal degeneration.

Figure 1

Protective role of the NRF2-KEAP1 pathway in genetic models of RP. (A) Nrf2 overexpression has shown to increase cone survival, preserve outer segment/inner segment structures, improve visual acuity, and enhance retinal activity by inhibiting lipid peroxidation. (B) PERK-mediated activation of NRF2 was found to inhibit photoreceptor degeneration, increase cone viability, and maintain outer segment structures. PERK = protein kinase R-like endoplasmic reticulum kinase, NRF2 = Nuclear factor erythroid-2-related factor, KEAP1 = Kelch-like ECH-associated protein 1, RP = Retinitis pigmentosa

Figure 2

Protective role of the NRF2-KEAP1 pathway in age-related retinal degeneration. (A) Age-related decline of NRF2 may pathologically contribute to retinal degeneration by disrupting mitochondrial-associated motility and metabolism of reactive oxygen species. (B) NRF2 mitigates drusen development, geographic atrophy, and choroidal neovascularization by enhancing lysosome-mediated lipid metabolism in the retinal pigment epithelium. NRF2 = Nuclear factor erythroid-2-related factor, KEAP1 = Kelch-like ECH-associated protein 1

Figure 3

Protective role of the NRF2-KEAP1 pathway in light-induced retinopathy. (A) NRF2 overexpression via sulforaphane treatment delays UVA-induced retinal degeneration by promoting the production of TRX, NQO1, and GSH in the retinal pigment epithelium. (B) NRF2 overexpression via RS9, MMF, and BE2 treatment confers protection against phototoxicity by inducing expression of HO-1 in photoreceptors. A positive feedback loop between Kit ligand (KITL) and NRF2 has been reported in the context of UVA damage. TRX: Thioredoxin; NQO1 = NAD(P)H quinone dehydrogenase 1, GSH = Glutathione, HO-1 = Heme oxidase 1, NRF2 = Nuclear factor erythroid-2-related factor, KEAP1 = Kelch-like ECH-associated protein 1

Figure 4

Protective role of the NRF2-KEAP1 pathway in oxygen-induced retinopathy. NRF2 promotes proper vascularization through both cell type-specific and general mechanisms. In retinal ganglion cells, NRF2 inhibits SEMA6a via HIF-1A stimulation. In Muller cells, NRF2 suppresses inflammatory cytokines. NRF2 was also found to maintain oxidation homeostasis by inhibiting ROS via NQO1 stimulation. Finally, VEGF has shown to play a multifaceted role in preserving vascularization and preventing pathological neovascularization through NRF2-mediated activation and inhibition, respectively. HIF-1A: Nox 2 = NADPH oxidase 2, NQO1 = NAD(P)H quinone dehydrogenase 1, HIF-1a = Hypoxia inducible factor 1 alpha, TNF-A = Tumor necrosis factor alpha; IL-1B = Interleukin 1 beta, MCP-1 = Monocyte chemoattractant protein 1, ICAM-1 = Intercellular adhesion molecule 1, VEGF = Vascular endothelial growth factor, NRF2 = Nuclear factor erythroid-2-related factor, KEAP1 = Kelch-like ECH-associated protein 1, ROS = Reactive oxygen species

Figure 5

Protective role of the nuclear factor erythroid-2-related factor-Kelch-like ECH-associated protein 1 pathway in ischemia-reperfusion injury. Nuclear factor erythroid-2-related factor improves retinal function by protecting retinal ganglion cells against apoptotic DNA cleavage