Ultraviolet B-induced Otx2 expression in lens epithelial cells promotes epithelial–mesenchymal transition

Yoshitomi, Yasuo; Osada, Hiromi; Satake, Haruka; Kojima, Masami; Saito-Takatsuji, Hidehito; Ikeda, Takayuki; Yoshitake, Yoshino; Ishigaki, Yasuhito; Kubo, Eri; Sekiya, Hiroshi; Yonekura, Hideto

doi:10.1242/bio.035691

Cited by 8 publications

(9 citation statements)

References 30 publications

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“…The study further provided reference exposure irradiance values for the cornea and lens, which could be used to evaluate the possible photochemical reactions caused by solar UV in laboratory studies. Furthermore, similar to the UV-B exposure irradiance results in this study, previous studies reported that such exposure caused damage to lens epithelial cells and corneal epithelial cells [9], [35]. However, the biological reaction under the UV-A exposure effects and the reaction of retinal epithelium cells generally occur at higher stated exposure levels, and whether similar reactions would occur under the exposure irradiance reported in this study has not been clarified and should be further investigated.…”

Section: Discussionmentioning

confidence: 45%

Solar Ultraviolet Exposure and Absorbed Irradiance of the Cornea and Anterior Chamber/Lens: A Monitoring Model Using Porcine Eyes in a Manikin

Hua

Chen

et al. 2020

IEEE Access

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Solar ultraviolet (UV) radiation is an unavoidable environmental and physical factor that contributes to a variety of eye diseases. Previous studies have mostly focused on the mechanism of eye damage caused by acute UV radiation. However, long-term and low-level day-today solar UV irradiance and absorption of UV ocular tissue induce chronic damage, and cumulative exposure over time may lead to age-related oculopathy. This study aimed to monitor the exposure of ocular tissue to sunlight and the amount of incident radiation absorbed. We attempted to simulate the actual natural exposure of representative ocular tissue to solar UV radiation. Therefore, in this study, a dual-detector spectrometer was used to measure the exposure, at a range of solar elevation angles (SEAs), of porcine eyes implanted into a manikin. The study found that the maximum solar UV irradiance exposure of the cornea was one-half the horizontal ambient exposure, while that of the anterior chamber/lens was one-fifth the horizontal ambient exposure. The absorption ratio decreased with increasing wavelength for the cornea and increased with increasing wavelength for the anterior chamber/lens. In conclusion, the study established a monitoring model using porcine eyes and determined the absolute and relative exposure/absorbed UV irradiance of ocular tissue at all SEAs in a context with high ambient solar UV. Furthermore, the study indicated that for individual ocular solar UV exposure, the ratio of absorbed to total exposure to solar UV irradiance varied due to changes in the SEA and sunlight path length throughout the day. These findings provide data on actual exposure and absorbed irradiance for future UV studies and might provide an exposure-based reference for cataractogenesis.

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Section: Discussionmentioning

confidence: 45%

Solar Ultraviolet Exposure and Absorbed Irradiance of the Cornea and Anterior Chamber/Lens: A Monitoring Model Using Porcine Eyes in a Manikin

Hua

Chen

et al. 2020

IEEE Access

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“…Expression of the Fn1 gene changed little after galactose treatment, but was suppressed by Atm inhibitors, suggesting that it may be involved in Atm-regulated EMT. When EMT is inducted in LECs, α-SMA is upregulated and LECs transform to fibroblast-like cells, compromising their differentiation into normal lens fiber cells [52]. These results suggest that galactose-induced EMT in LECs is one of the causes of opacity, and that blockade of this axis with Atm inhibition normalizes cell differentiation, decreasing opacity.…”

Section: Plos Onementioning

confidence: 89%

Atm inhibition decreases lens opacity in a rat model of galactose-induced cataract

et al. 2022

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Cataract causes vision loss and blindness due to formation of opacities of the lens. The regulatory mechanisms of cataract formation and progression remain unclear, and no effective drug treatments are clinically available. In the present study, we tested the effect of ataxia telangiectasia mutated (Atm) inhibitors using an ex vivo model in which rat lenses were cultured in galactose-containing medium to induce opacity formation. After lens opacities were induced by galactose, the lenses were further incubated with the Atm inhibitors AZD0156 or KU55933, which decreased lens opacity. Subsequently, we used microarray analysis to investigate the underlying molecular mechanisms of action, and extracted genes that were upregulated by galactose-induced opacity, but not by inhibitor treatment. Quantitative measurement of mRNA levels and subsequent STRING analysis revealed that a functional network consisting primarily of actin family and actin-binding proteins was upregulated by galactose treatment and downregulated by both Atm inhibitors. In particular, Acta2 is a known marker of epithelial-mesenchymal transition (EMT) in epithelial cells, and other genes connected in this functional network (Actn1, Tagln, Thbs1, and Angptl4) also suggested involvement of EMT. Abnormal differentiation of lens epithelial cells via EMT could contribute to formation of opacities; therefore, suppression of these genes by Atm inhibition is a potential therapeutic target for reducing opacities and alleviating cataract-related visual impairment.

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“…Itdidnot show better chaperonefunction against aggregation ofGAPDH,α-SMA and laminin γ2 byCRYAA-WT at the physiologicaltemperature asdescribed previously [32]. Comparedto CRYAA-WT, chaperonefunctionin uenced by CRYAA-E83E showed theability promoteGAPDHaggregation; suppress α-SMA and FNaggregation; noin uencesagainst laminin γ2 aggregation.Chaperone functionmeasured byaggregation assay in uenced by 42℃treatment and UVirradiationwere rst constructed in this study.The heat treatmentresponseoccurred in HLE B-3 cells after treatedwith 42℃ for4 h. HLEB-3 cell lysates transfected withCRYAA-WT treated with42℃ showedlittle impact on chaperonefunction; HLE B-3 celllysatestransfected with CRYAA-E83E treatedwith 42℃ showeddecreasedchaperone function against GAPDHaggregation, UV has been proved to up-regulate the expressionlevelofEMT-related molecules, such as FN, α-SMAandNcadherin [26,33,34]. UV couldalso down-regulated theexpressionlevel of lens ber cell markergene CRYAA in lensepithelial cellsof mouse [26].Laminin γ2 promotedmetastasis in lungadenocarcinoma via EMT [31].…”

Section: Discussionmentioning

confidence: 99%

“…Epithelial-mesenchymal transition (EMT) has been widelystudiedinthe posterior cataract, but there's no report showedtherelationshipbetween EMT and ARC. In vitro experiments showedthatUVB couldupregulate expression levels of OrthodenticleHomeobox 2(Otx2) inSRA cell lines, and the increased Otx2 inducedEMT andup-regulatedSmooth muscle actin (SMA) [26]. Laminin γ2 is animportantstructuralcomponent of the epithelial BM in variousnormaltissues [27].…”

Section: Introductionmentioning

confidence: 99%

A novel silent mutation E83E of αA-crystallin in age-related cataract with impaired chaperone function

Song

Liu

Sun

et al. 2020

Preprint

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Background Age-related cataract (ARC) is the leading cause of blindness of the aged, influenced by environmental factors and genetic factors. However, it is scanty in gene mutation studies. The study aims to expand knowledge of etiology of ARC. Methods Peripheral blood samples of ARC patients were collected to screen αA-crystallin (CRYAA) gene mutations by single strand conformation polymorphism assay. Cell morphology, protein expression level and chaperone function of CRYAA in HLE B-3 cell line influenced by mutant CRYAA were next analyzed. Chaperone function of mutant CRYAA was measured by aggregation assay in physiological status, heat treatment (42℃) and ultraviolet (UV) treatment. Cell morphology and protein expression level effected by UV in human lens epithelial B3 (HLE B-3) cells and human anterior lens capsules (ALCs) were further analyzed. Results We identified a novel silent mutation in CRYAA (c.249G > A, p.E83E) among 300 ARC patients. CRYAA-E83E may up-regulate the CRYAA expression levels of both mRNA and protein, and change the distribution of CRYAA in HLE B-3 cells. Compared to wild type CRYAA (CRYAA-WT), CRYAA-E83E showed lower chaperone function after 42℃ heat treatment and UV treatment. Meanwhile, after UV treatment, HLE B-3 cells and lens epithelial cells in human ALCs showed irregular and flatten morphology; decreased CRYAA expression levels; increased laminin γ2 expression levels, and changed epithelial-mesenchymal transition (EMT) related protein expression levels. Conclusions The E83E mutation of CRYAA is a potential pathogenic mutation, considering its influence on the expression level, intracellular distribution and chaperone function of CRYAA.

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Ultraviolet B-induced Otx2 expression in lens epithelial cells promotes epithelial–mesenchymal transition

Cited by 8 publications

References 30 publications

Solar Ultraviolet Exposure and Absorbed Irradiance of the Cornea and Anterior Chamber/Lens: A Monitoring Model Using Porcine Eyes in a Manikin

Solar Ultraviolet Exposure and Absorbed Irradiance of the Cornea and Anterior Chamber/Lens: A Monitoring Model Using Porcine Eyes in a Manikin

Atm inhibition decreases lens opacity in a rat model of galactose-induced cataract

A novel silent mutation E83E of αA-crystallin in age-related cataract with impaired chaperone function

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