The Regulation of NFE2L2 (NRF2) Signalling and Epithelial-to-Mesenchymal Transition in Age-Related Macular Degeneration Pathology

Hyttinen, Juha M. T.; Kannan, Ram; Felszeghy, Szabolcs; Niittykoski, Minna; Salminen, Antero; Kaarniranta, Kai

doi:10.3390/ijms20225800

Cited by 52 publications

(35 citation statements)

References 264 publications

(336 reference statements)

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“…Some compounds, primarily exogenous compounds, including polyphenols [23], flavonoids [24], terpenoids [25], or noncoding RNAs [26] have been reported to be Nrf2 activators or inducers. These compounds may have key roles in protecting ocular cells from oxidative stress, inflammation, and fibrosis [27,28]. The participation in the mechanism and antioxidative capacity of Nrf2 occurs in several systemic diseases, including respiratory disease [29], cardiovascular, and cerebrovascular disease [30], degenerative disease, tumors [31], and ocular disease.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Zheng

2020

Med Sci Monit

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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.

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Section: Introductionmentioning

confidence: 99%

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

Wang

Zheng

2020

Med Sci Monit

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“…Intraretinal migration of RPE cells reportedly occurs after the epithelial–mesenchymal transition (EMT) [ 28 , 29 ]. It has been shown that RPE cells transdifferentiate from an epithelial phenotype to a migratory fibroblastic phenotype during EMT [ 29 ], thus revealing that RPE reportedly lost epithelial markers, such as E-cadherin and CK18, and acquired mesenchymal markers, such as N-cadherin, α-smooth muscle actin, and vimentin [ 30 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Involvement of the Retinal Pigment Epithelium in the Development of Retinal Lattice Degeneration

Mizuno

Fukumoto

Sato

et al. 2020

IJMS

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Lattice degeneration involves thinning of the retina that occurs over time. Here we performed an immunohistological study of tissue sections of human peripheral retinal lattice degeneration to investigate if retinal pigment epithelium (RPE) cells are involved in the pathogenesis of this condition. In two cases of retinal detachment with a large tear that underwent vitreous surgery, retinal lattice degeneration tissue specimens were collected during surgery. In the obtained specimens, both whole mounts and horizontal section slices were prepared, and immunostaining was then performed with hematoxylin and antibodies against glial fibrillary acidic protein (GFAP), RPE-specific protein 65 kDa (RPE65), pan-cytokeratin (pan-CK), and CK18. Hematoxylin staining showed no nuclei in the center of the degenerative lesion, thus suggesting the possibility of the occurrence of apoptosis. In the degenerative lesion specimens, GFAP staining was observed in the center, RPE65 staining was observed in the slightly peripheral region, and pan-CK staining was observed in all areas. However, no obvious CK18 staining was observed. In a monkey retina used as the control specimen of a normal healthy retina, no RPE65 or pan-CK staining was observed in the neural retina. Our findings suggest that migration, proliferation, and differentiation of RPE cells might be involved in the repair of retinal lattice degeneration.

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“…Exposure of RPE cells to these pro-inflammatory cytokines has been shown to downregulate the expression of genes that are critical for normal RPE functioning (RPE65, CDH1, RDH5) whilst upregulating genes (ZEB1 and SNAI1) associated with epithelial to mesenchymal transition (EMT) [117]. The EMT of RPE cells is associated with the development of sub-retinal fibrosis which contribute to sight loss in AMD; further evidence for the role of oxidative stress and inflammation in retinopathies [118,119]. Aβ, which accumulates in aged eyes and in eyes with AMD [48], is another potential source of retinal inflammation, and has been shown to disrupt the RPE barrier via direct and indirect mechanisms, including elevated production of reactive oxygen species, that results in diminished trans-epithelial resistance and barrier integrity [120,121].…”

Section: Role Of Timp-3 In Retinal and Brain Inflammationmentioning

confidence: 99%

The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain

Dewing

Carare

Lotery

et al. 2019

Cells

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Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer's disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer's patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer's-linked amyloid-beta (Aβ) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Aβ. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.

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The Regulation of NFE2L2 (NRF2) Signalling and Epithelial-to-Mesenchymal Transition in Age-Related Macular Degeneration Pathology

Cited by 52 publications

References 264 publications

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

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

Involvement of the Retinal Pigment Epithelium in the Development of Retinal Lattice Degeneration

The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain

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