Endoplasmic Reticulum Stress Regulates Scleral Remodeling in a Guinea Pig Model of Form-Deprivation Myopia

Zhu, Chengcheng; Chen, Qingzhong; Yuan, Ying; Li, Min; Ke, Bilian

doi:10.1155/2020/3264525

Cited by 10 publications

(7 citation statements)

References 48 publications

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“…The most common animal models of myopia are form-deprivation myopia (FDM) and lens-induced myopia (LIM) [ 2 – 4 ]. Recently, our team found that mice with LIM showed endoplasmic reticulum (ER) stress in the sclera, which is similar to the results of other researchers using the FDM model [ 5 , 6 ]. Furthermore, we previously showed that scleral ER stress causes myopia [ 5 , 6 ].…”

Section: Introductionsupporting

confidence: 86%

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Establishment of a novel ER-stress induced myopia model in mice

Kang,

Ikeda,

Yang

et al. 2023

Eye and Vis

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Background Recent studies have indicated a strong correlation between endoplasmic reticulum (ER) stress and myopia and that eyedrops containing the ER stress inducer tunicamycin (Tm) can induce myopic changes in C57BL/6 J mice. Therefore, this study aimed to create a new myopia model using Tm eyedrops and to explore the mechanism of ER stress-mediated myopia development. Methods Three-week-old C57BL/6 J mice were treated with different concentrations (0, 25, 50, and 100 μg/mL) and/or number of applications (zero, one, three, and seven) of Tm eyedrops. Refraction and axial length (AL) were measured before and one week after Tm treatment. Scleral collagen alterations were evaluated under polarised light after picrosirius red staining. ER stress-related indicators, such as the expression of collagen I and cleaved collagen were detected using Western blotting. Results Compared with the control group, mice administered eyedrops with 50 μg/mL Tm only once showed the greatest myopic shifts in refraction and AL elongation and reduced scleral expression of collagen I. Picrosirius red staining showed a lower percentage of bundled collagen in the Tm group. Expression of ER-stress indicators increased in the Tm groups. Furthermore, optimised administration of Tm induced matrix metalloproteinase-2 (MMP2) expression in the sclera, which plays a major role in collagen degradation. Conclusions We have demonstrated that ER stress in the sclera is involved in myopia progression. Tm eyedrops induced myopic changes, loosening of the scleral collagen and decreased expression of collagen I. This process may be associated with ER stress in the sclera, which upregulates the expression of MMP2 leading to collagen degradation.

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Section: Introductionsupporting

confidence: 86%

“…Recently, our team found that mice with LIM showed endoplasmic reticulum (ER) stress in the sclera, which is similar to the results of other researchers using the FDM model [ 5 , 6 ]. Furthermore, we previously showed that scleral ER stress causes myopia [ 5 , 6 ]. This clearly indicates a correlation between myopia and ER stress.…”

Section: Introductionsupporting

confidence: 86%

Establishment of a novel ER-stress induced myopia model in mice

Kang,

Ikeda,

Yang

et al. 2023

Eye and Vis

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“…The Col1a1 and Mmp2 genes have been reported to encode the extracellular matrix component collagen and are engaged in extracellular matrix remodeling in the sclera [31,32]. In addition, the proteins encoded by Col1a1 and Mmp2 are involved in angiogenesis and the myopia pathway (among other activities) in mice and guinea pigs [33][34][35][36]. Here, we found that the expression levels of these two genes were upregulated in the retina after the intravitreal injection of brimonidine.…”

Section: Discussionmentioning

confidence: 66%

Intravitreal brimonidine inhibits form-deprivation myopia in guinea pigs

Yang

et al. 2021

Eye and Vis

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Background The use of ocular hypotensive drugs has been reported to attenuate myopia progression. This study explores whether brimonidine can slow myopia progression in the guinea pig form-deprivation (FD) model. Methods Three-week-old pigmented male guinea pigs (Cavia porcellus) underwent monocular FD and were treated with 3 different methods of brimonidine administration (eye drops, subconjunctival or intravitreal injections). Four different concentrations of brimonidine were tested for intravitreal injection (2 μg/μL, 4 μg/μL, 20 μg/μL, 40 μg/μL). All treatments continued for a period of 21 days. Tonometry, retinoscopy, and A-scan ultrasonography were used to monitor intraocular pressure (IOP), refractive error and axial length (AL), respectively. On day 21, guinea pigs were sacrificed for RNA sequencing (RNA-seq) to screen for associated transcriptomic changes. Results The myopia model was successfully established in FD animals (control eye vs. FD eye, respectively: refraction at day 20, 0.97 ± 0.18 D vs. − 0.13 ± 0.38 D, F = 6.921, P = 0.02; AL difference between day 0 and day 21, 0.29 ± 0.04 mm vs. 0.45 ± 0.03 mm, F = 11.655, P = 0.004). Among the 3 different brimonidine administration methods, intravitreal injection was the most effective in slowing myopia progression, and 4 μg/μL was the most effective among the four different concentrations of brimonidine intravitreal injection tested. The AL and the refraction of the brimonidine intravitreal injection group was significantly shorter or more hyperopic than those of other 2 groups. Four μg/μL produced the smallest difference in AL and spherical equivalent difference values. FD treatment significantly increased the IOP. IOP was significantly lower at 1 day after intravitreal injections which was the lowest in FD eye of intravitreal injection of brimonidine. At day 21, gene expression analyses using RNA-seq showed upregulation of Col1a1 and Mmp2 expression levels by intravitreal brimonidine. Conclusions Among the 3 different administration methods, intravitreal injection of brimonidine was the most effective in slowing myopia progression in the FD guinea pig model. Intravitreal brimonidine at 4 μg/μL significantly reduced the development of FD myopia in guinea pigs. Expression levels of the Col1a1 and Mmp2 genes were significantly increased in the retinal tissues of the FD-Inj-Br group.

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“…We hypothesized that scleral ER stress participates in the onset and progression of axial elongation during the myopia development as axial elongation is a change in the organ size, which is probably achieved by remodeling of ECM in sclera. In fact, there have been recent reports indicating that ER stress occurs in the myopic sclera using a form-deprivation myopia model in guinea pig 15 . To elucidate the hypothesis, we used pharmacological and genetic methods to induce/inhibit ER stress in a mouse model of LIM and tested its effect on the myopia progression.…”

Section: Introductionmentioning

confidence: 99%

Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

et al. 2022

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Axial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.

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Endoplasmic Reticulum Stress Regulates Scleral Remodeling in a Guinea Pig Model of Form-Deprivation Myopia

Cited by 10 publications

References 48 publications

Establishment of a novel ER-stress induced myopia model in mice

Establishment of a novel ER-stress induced myopia model in mice

Intravitreal brimonidine inhibits form-deprivation myopia in guinea pigs

Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes

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