1. Academic Validation
  2. High-glucose induces retinal pigment epithelium mitochondrial pathways of apoptosis and inhibits mitophagy by regulating ROS/PINK1/Parkin signal pathway

High-glucose induces retinal pigment epithelium mitochondrial pathways of apoptosis and inhibits mitophagy by regulating ROS/PINK1/Parkin signal pathway

  • Biomed Pharmacother. 2019 Mar;111:1315-1325. doi: 10.1016/j.biopha.2019.01.034.
Yuanping Zhang 1 Xiaoting Xi 2 Yan Mei 3 Xueying Zhao 1 Liqiong Zhou 1 Minjun Ma 1 Sili Liu 1 Xu Zha 1 Yanni Yang 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, The 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road, Kunming Yunnan, China.
  • 2 Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical University, Xichang Road 295, Kunming, Yunnan, China.
  • 3 Department of Ophthalmology, The First people's Hospital of Yunnan Province, Jinbi Road, Kunming, Yunnan, China.
  • 4 Department of Ophthalmology, The 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road, Kunming Yunnan, China. Electronic address: 18206876087@163.com.
Abstract

Diabetic retinopathy (DR) seriously endangers human beings' health, uncovering the underlying mechanism might help to cure DR. In this study, we found that the effects of glucose on retinal pigment epithelium (RPE) varies in a dose dependent manner, high-glucose (50mM) promotes Reactive Oxygen Species (ROS) generation and cell Apoptosis, inhibits cell Mitophagy as well as proliferative abilities, while low-glucose (15mM) induces ROS production and cell Mitophagy, but has little impacts on cell Apoptosis and proliferation. Of note, the toxic effects of high-glucose (50mM) on RPE are alleviated by ROS scavengers and aggravated by Autophagy Inhibitor 3-methyladenine (3-MA) or Mitophagy inhibitor cyclosporin A (CsA). High-glucose (50mM) induced ROS generation is merely eliminated by ROS scavengers instead of Mitophagy or Autophagy Inhibitor. We also proved that high-glucose (50mM) inhibits cell proliferation and promotes cell Apoptosis by regulating ROS mediated inhibition of Mitophagy. In addition, Mitophagy associated proteins PINK1 and Parkin are downregulated by high-glucose (50mM) or hydrogen peroxide treatments, which are reversed by ROS scavengers. Of note, Knock-down of PINK1 decreases phospharylated Parkin instead of total Parkin levels in RPE. Intriguingly, high-glucose's inhibiting effects on cell Mitophagy as well as proliferation and its promoting effects on cell Apoptosis are reversed by either PINK1 or Parkin overexpression. Therefore, we concluded that high-glucose promotes RPE Apoptosis and inhibits cell proliferation as well as Mitophagy by regulating ROS mediated inactivation of ROS/PINK1/Parkin signal pathway.

Keywords

Apoptosis; Diabetic retinopathy; High-glucose; Mitophagy; RPE.

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