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Mst1 facilitates hyperglycemia-induced retinal pigmented epithelial cell apoptosis by evoking mitochondrial stress and activating the Smad2 signaling pathway

  • Bing Wei
  • Min Wang
  • Wei Hao
  • Xiangdong HeEmail author
Original Paper
  • 35 Downloads

Abstract

Hyperglycemia induces retinal pigmented epithelial cell apoptosis and mitochondrial stress via poorly understood mechanisms. The goal of our current study is to explore whether mammalian sterile 20-like kinase 1 (Mst1) is involved in the pathogenesis of hyperglycemia-mediated retinal pigmented epithelial cell apoptosis by triggering mitochondrial abnormalities and activating the Smad2 signaling pathway. Retinal pigmented epithelial ARPE-19 cells were presented with a high-glucose challenge in vitro. Cell viability and apoptosis were measured via western blotting, ELISAs, and immunofluorescence assays. Mitochondrial function was detected via JC-1 staining, mitochondrial ROS flow cytometry, western blotting, and ELISAs. Loss- and gain-of-function assays were performed via cell transfection and transduction with Mst1 siRNA and Smad2 adenovirus, respectively. The results indicated that hyperglycemia treatment upregulated the levels of Mst1, an effect that was accompanied by an increase in ARPE-19 cell apoptosis. Loss of Mst1 attenuated hyperglycemia-induced cell apoptosis, and this effect seemed to be associated with mitochondrial protection. In response to hyperglycemia stimulus, mitochondrial stress was noted in ARPE-19 cells, including mitochondrial ROS overproduction, mitochondrial respiratory metabolism dysfunction, mitochondrial fission/fusion imbalance, and mitochondrial apoptosis activation. Further, we provided evidence to support the crucial role played by Smad2 in promoting Mst1-mediated cell apoptosis and mitochondrial stress. Overexpression of Smad2 abrogated the beneficial effects of Mst1 deletion on ARPE-19 cell viability and mitochondrial protection. Altogether, our results identified Mst1 as a novel mediator controlling the fate of retinal pigmented epithelial cells and mitochondrial homeostasis via the Smad2 signaling pathway. Based on this finding, strategies to repress Mst1 upregulation and block Smad2 activation are vital to alleviate hyperglycemia-mediated retinal pigmented epithelial cell damage.

Keywords

Retinal pigmented epithelial cell Mitochondria Mst1 Smad2 

Notes

Authors’ contributions

WB, XDH, and MW made substantial contributions to the concept and design of the present study, XDH, WB, MW, and WH contributed to the performance of experiments, data analysis and interpretation, and manuscript writing.

Funding

This work is supported by the 2016 Liaoning Provincial Natural Science Fund Guidance Plan Project (No. 201602383).

Compliance with ethical standards

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare that they have no conflict interest.

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Copyright information

© Cell Stress Society International 2019

Authors and Affiliations

  1. 1.Department of MedicineHe UniversityShenyang CityChina

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