Cadmium toxicity toward autophagy through ROS-Activated GSK-3β in mesangial cells

Sheng Hao Wang, Yung Luen Shih, Tai Chin Kuo, Wun-Chang Ko, Chwen Ming Shih

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

We previously demonstrated that cadmium (Cd) is able to induce autophagic cell death through a calcium-extracellular signal-regulated kinase pathway. Here, the object of this study is to investigate the role of glycogen synthase kinase-3β (GSK-3β) in the induction of autophagy. After treatment with Cd, MES-13 mesangial cells were determined to have undergone autophagy based on the formation of acidic vesicular organelles and autophagosomes as well as on the processing of microtubule-associated protein 1 light chain 3, using flow cytometry with acridine orange staining, electron microscopy, and immunoblot, respectively. Use of the GSK-3β inhibitor SB 216763 or the small interfering RNA technique to knockdown the expression of GSK-3β resulted in a decrease of Cd-induced autophagy. In contrast, overexpression of GSK-3β by transient transfection potentiated Cd toxicity toward the mesangial cells, suggesting that GSK-3β plays a crucial role in regulating Cd-induced autophagy. Moreover, a decrease of the phosphorylated level at Ser9 of GSK-3β was observed by immunoblot after treatment with Cd, indicating GSK-3β was activated by Cd. This phenomenon was reversed by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC), demonstrated that ROS might activate GSK-3β. In fact, intracellular hydrogen peroxide (H 2 O 2) was 2.6-fold elevated after 3 h of exposure to Cd. Both Cd-induced ROS bursts and autophagy were reduced by NAC and vitamin E. In summary, this study demonstrated that, in MES-13 mesangial cells, Cd-induced autophagy was mediated through the ROS-GSK-3β signaling pathway.

Original languageEnglish
Pages (from-to)124-131
Number of pages8
JournalToxicological Sciences
Volume108
Issue number1
DOIs
Publication statusPublished - 2009

Keywords

  • Autophagy
  • Cadmium
  • GSK-3β
  • Mesangial cells
  • ROS

ASJC Scopus subject areas

  • Toxicology

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