IMR Press / FBL / Volume 27 / Issue 2 / DOI: 10.31083/j.fbl2702038
Open Access Original Research
Endoplasmic reticulum stress as a novel target to inhibit transdifferentiation of human retinal pigment epithelial cells
Sha Ouyang1,2,3,4Dan Ji2,3Shikun He4,*Xiaobo Xia2,3,*
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1 Department of Ophthalmology, The Third Xiangya Hospital, Central South University, 410000 Changsha, Hunan, China
2 Eye Center of Xiangya Hospital, Central South University, 410008 Changsha, Hunan, China
3 Hunan Key Laboratory of Ophthalmology, 410008 Changsha, Hunan, China
4 Department of Pathology, USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
*Correspondence: (Shikun He); (Xiaobo Xia)
Academic Editor: Graham Pawelec
Front. Biosci. (Landmark Ed) 2022, 27(2), 38;
Submitted: 31 August 2021 | Revised: 7 December 2021 | Accepted: 12 December 2021 | Published: 24 January 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: The epithelial to mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a critical event in the pathogenesis of proliferative vitreoretinopathy and neovascular age-related macular degeneration, which are the leading causes of severe vision loss. Endoplasmic reticulum (ER) stress has been implicated in the EMT of many cell types and various ocular diseases. However, the relationship between ER stress and EMT in RPE cells remains unknown. Therefore, in the study, we explored the impact of ER stress on EMT in RPE cells. Methods: Different concentrations of tunicamycin (TM) and thapsigargin (TG) were used to induce ER stress in human RPE cells. The expression of epithelial marker, mesenchymal markers and some of genes/proteins involved in TGF-β/Smad signaling were analized by qPCR, western blot or immunostaining at the condition with or without stimulation of TGF-β2 (10 ng/mL). Boyden chamber and scratch assay were used to evaluate the migration of RPE cells, while cell viability and apoptosis of RPE cells were measured by MTT and TUNEL assay, respectively. Results: Treatment of RPE cells with TM and TG (24 h) reduced the expression of α -SMA and FN, and increased the expression of Occludin in a dose dependent manner at protein level, which was highly associated with the expression of GRP78. Treatment with TGF-β2 significantly increased the expression of α-SMA and FN, and decreased the expression of Occludin both in protein and mRNA levels, which was significantly inhibited by a 4h pre-treatment with TM. In addition, the expression of TGF-βRII and Smad2/3, and mRNAs of TGF-βRII and Smad3 were also decreased by the TM treatment. TM-induced ER stress inhibited RPE cell migration, and high concentrations of TM and TG reduced cell viability and induced apoptosis of RPE cells. Conclusions: Chemical induction of ER stress inhibited EMT and migration in RPE cells, possibly by inactivation of TGF-β signaling, suggesting that regulation of ER stress in RPE cells may be a new approach to prevent the development of intraocular fibrosis.

Endoplasmic reticulum stress
Epithelial-mesenchymal transition
Cell movements
TGF-β signaling
Retinal pigment epithelial cells
Fig. 1.
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