Activation of autophagy inhibits epithelial to mesenchymal transition process of human lens epithelial cells induced by high glucose conditions

Li, Ji; Ye, Wei; Xu, W.; Chang, Tianfang; Zhang, Luning; Ma, Jiyuan; Pei, Rui; He, Mengmei; Zhou, Jian

doi:10.1016/j.cellsig.2020.109768

Cited by 20 publications

(14 citation statements)

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“…Impairment of autophagy flux in LECs and fiber cells may result in the formation of congenital cataracts, age-related cataracts, and diabetic cataracts (Morishita et al 2013 ; Liu et al 2020 ; Andley and Goldman 2016 ). In the present study, autophagic activity was attenuated both in LECs of diabetic rats and in HLE-B3 cells stimulated with high glucose concentrations, consistent with the findings of many other studies (Chen et al 2021 ; Li et al 2020 ). However, Liu has showed that autophagy changes from activation at the early stage to subsequent inhibition in the LECs of mice under high-glucose conditions (Liu et al 2020 ).…”

Section: Discussionsupporting

confidence: 93%

“…The correlation between the EMT of LECs and diabetic cataracts has been reported (Zhang et al 2017;Du et al 2017;. We have also confirmed that highglucose stimulation induces the EMT of LECs in vitro (Han et al 2018;Li et al 2020;Ye et al 2020). In the present study, we have further verified that LECs undergo the EMT under high-glucose conditions both in vivo and in vitro.…”

Section: Discussionsupporting

confidence: 87%

“…Nevertheless, Wang et al (Han et al 2019) have reported that the inhibition of autophagy induces the EMT in RAS-mutated cells by activating the NF-κB pathway via SQSTM1/p62. As showed in our previous study, inhibition of autophagy enhanced the EMT in HLE-B3 cells under high glucose conditions via interactions of SQSTM1/p62 and Snail (Li et al 2020). Nonetheless, other possible mechanisms regulating autophagy and EMT remain to be discovered.…”

Section: Introductionmentioning

confidence: 72%

“…In addition, autophagy facilitates cardiac differentiation by degrading NICD (Jia et al 2014 ). In addition to selective autophagy mediated by SQSTM1/p62 (Li et al 2020 ), autophagy degrades proteins by promoting interactions with LC3 (Shvets et al 2008 ). Our study suggests that rapamycin inhibits the EMT by increasing autophagic activity and then promotes the degradation of Notch1 through both the interaction of LC3 and SQSTM1/p62 with Notch1.…”

Section: Discussionmentioning

confidence: 99%

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The interaction between autophagy and the epithelial-mesenchymal transition mediated by NICD/ULK1 is involved in the formation of diabetic cataracts

Yang

et al. 2022

Mol Med

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Background Cataracts are the leading cause of blindness and a common ocular complication of diabetes. The epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) and altered autophagic activity occur during the development of diabetic cataracts. The disturbed interaction of autophagy with EMT in LECs stimulated by high glucose levels may participate in cataract formation. Methods A rat diabetic cataract model induced by streptozotocin (STZ) and human lens epithelial cells (HLE-B3) stimulated with a high glucose concentration were employed in the study. These models were treated with rapamycin (an inhibitor of mammalian target of rapamycin (mTOR)), and N-(N-[3,5-difluorophenacetyl]-1-alanyl)-S-phenylglycine t-butyl ester (DAPT, an inhibitor of γ-secretase) alone or in combination. Lens opacity was observed and photographed under a slit-lamp microscope. Histological changes in paraffin sections of lenses were detected under a light microscope after hematoxylin and eosin staining. Alterations of autophagosomes in LECs were counted and evaluated under a transmission electron microscope. The expression levels of proteins involved in the EMT, autophagy, and the signaling pathways in LECs were measured using Western blotting and immunofluorescence staining. Cell migration was determined by performing transwell and scratch wound assays. Coimmunoprecipitation (Co-IP) was performed to verify protein-protein interactions. Proteins were overexpressed in transfected cells to confirm their roles in the signaling pathways of interest. Results In LECs, a high glucose concentration induces the EMT by activating Jagged1/Notch1/Notch intracellular domain (NICD)/Snail signaling and inhibits autophagy through the AKT/mTOR/unc 51-like kinase 1 (ULK1) signaling pathway in vivo and in vitro, resulting in diabetic cataracts. Enhanced autophagic activity induced by rapamycin suppressed the EMT by inducing Notch1 degradation by SQSTM1/p62 and microtubule-associated protein light chain 3 (LC3) in LECs, while inhibition of the Notch signaling pathway with DAPT not only prevented the EMT but also activated autophagy by decreasing the levels of NICD, which bound to ULK1, phosphorylated it, and then inhibited the initiation of autophagy. Conclusions We describe a new interaction of autophagy and the EMT involving NICD/ULK1 signaling, which mediates crosstalk between these two important events in the formation of diabetic cataracts. Activating autophagy and suppressing the EMT mutually promote each other, revealing a potential target and strategy for the prevention of diabetic cataracts.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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The interaction between autophagy and the epithelial-mesenchymal transition mediated by NICD/ULK1 is involved in the formation of diabetic cataracts

Yang

et al. 2022

Mol Med

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“…Nevertheless, Wang et al ) demonstrated that inhibition of autophagy induces EMT in RAS-mutated cells by triggering the NF-κB pathway via SQSTM1/p62. Our previous study revealed that inhibition of autophagy can enhance EMT via interactions of SQSTM1/p62 and Snail in HLE-B3 cells under high glucose conditions (Li et al 2020). Nonetheless, other possible mechanisms regulating autophagy and EMT remain to be discovered.…”

Section: Introductionmentioning

confidence: 96%

The Interaction Between Autophagy and Epithelial-Mesenchymal Transition via NICD/ULK1 is Involved in the Formation of Diabetic Cataracts

Yang

et al. 2022

Preprint

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BackgroundCataracts are the leading cause of blindness and a common ocular complication of diabetes. Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) and altered autophagic activity occur during the development of diabetic cataracts. The disturbed interaction of autophagy with EMT in LECs stimulated by high glucose may participate in cataract formation.MethodsWe employed a diabetic rat model induced by streptozotocin (STZ) and human lens epithelial HLE-B3 cells stimulated with high glucose to observe the interaction of autophagy and EMT. Lens opacification was observed by slit-lamp bio-microscope, and the histological changes of lenses were detected under light microscope through paraffin section staining with hematoxylin-eosin. The autophagosomes in lens epithelial cells in vivo and in vitro were quantified under a transmission electron microscopy. The expression of EMT and autophagy markers were measured by Western blotting and immunofluorescence staining. Cell migration was determined by transwell and scratch wound assays. Co-immunoprecipitation (Co-IP) was performed to verify protein-protein interactions. Overexpression of proteins were induced by cell transfection. ResultsIn LECs, high glucose induces EMT by activating Jagged1/Notch1/NICD/Snail and inhibits autophagy through the AKT/mTOR/ULK1 signaling pathways in vivo and in vitro, resulting in diabetic cataracts. Enhanced autophagic activity by rapamycin, an mTOR inhibitor, suppressed EMT by degrading Notch1 through SQSTM1/p62 and LC3 in LECs, while inhibition of the Notch signaling pathway by DAPT, an inhibitor of γ-secretase, not only prevented EMT but also activated autophagy by downregulating the expression of NICD, which binds to ULK1, phosphorylates it, and then inhibits autophagic initiation.ConclusionsWe demonstrated a new interaction of autophagy and EMT involving NICD/ULK1, which mediates crosstalk between these two important events in the formation of diabetic cataracts. Activating autophagy and suppressing EMT mutually promote each other, identifying a potential target and strategy for the prevention of diabetic cataracts.

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Promising Pharmacological Interventions for Posterior Capsule Opacification: A Review

Liu,

Dong,

et al. 2024

Global Challenges

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Phacoemulsification combined with intraocular lens implantation is the primary treatment for cataract. Although this treatment strategy benefits patients with cataracts, posterior capsule opacification (PCO) remains a common complication that impairs vision and affects treatment outcomes. The pathogenesis of PCO is associated with the proliferation, migration, and fibrogenesis activity of residual lens epithelial cells, with epithelial–mesenchymal transition (EMT) serving as a key mechanism underlying the condition. Transforming growth factor‐beta 2 (TGF‐β2) is a major promotor of EMT, thereby driving PCO development. Most studies have shown that drugs and miRNAs mitigate EMT by inhibiting, clearing, or eliminating LECs. In addition, targeting EMT–related signaling pathways in TGF‐β2–stimulated LECs has garnered attention as a research focus. This review highlights potential treatments for PCO and details the mechanisms by which drugs and miRNAs counter EMT.

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Activation of autophagy inhibits epithelial to mesenchymal transition process of human lens epithelial cells induced by high glucose conditions

Cited by 20 publications

References 33 publications

The interaction between autophagy and the epithelial-mesenchymal transition mediated by NICD/ULK1 is involved in the formation of diabetic cataracts

The interaction between autophagy and the epithelial-mesenchymal transition mediated by NICD/ULK1 is involved in the formation of diabetic cataracts

The Interaction Between Autophagy and Epithelial-Mesenchymal Transition via NICD/ULK1 is Involved in the Formation of Diabetic Cataracts

Promising Pharmacological Interventions for Posterior Capsule Opacification: A Review

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