Nickel(II) induced JNK activation-regulated mitochondria-dependent apoptotic pathway leading to cultured rat pancreatic β-cell death.

Hsi-Chin Wu, Ching-Yao Yang, Dong-Zong Hung, Chin-Chuan Su, Kuo-Liang Chen, Cheng-Chieh Yen, Tsung-Jung Ho, Yi-Chang Su, Chun-Fa Huang, Chun-Hung Chen, Ling-Mei Tsai, Ya-Wen Chen

Department of Urology, China Medical University Hospital, No. 2, Yuh-Der Rd., Taichung 404, Taiwan.

Toxicology 2011 Nov 18

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Nickel (Ni), a well-known toxic metal, is widely used in electroplating and alloy production. It is also significantly implicated in industrial and environmental pollution caused by uncontrolled industrial and municipal discharges. In this study, we characterized and investigated the cytotoxic effects of Ni exposure and their probable toxicological mechanisms in the pancreatic β-cells. The results showed that it was significantly decreased cell viability after exposing pancreatic β-cell-derived RIN-m5F cells to NiCl(2) for 24h in a dose-dependent manner. NiCl(2) also increased sub-G1 hypodiploid cells and Annexin V-Cy3 binding population in RIN-m5F cells, indicating that it has apoptosis-inducing ability. Moreover, the exposure of RIN-m5F cells to NiCl(2) induced distinct signals of mitochondria-dependent apoptosis, including mitochondrial dysfunction (the disruption of mitochondrial membrane potential (MMP) and increase in mitochondrial cytochrome c release into the cytosol), Bak and Bid mRNA up-regulation, and activation of caspase-3, caspase-7, and caspase-9, and poly(ADP-ribose) polymerase (PARP) degradation. In addition, NiCl(2) also markedly induced the activation of c-Jun N-terminal kinases (JNK), but not of extracellular signal-regulated kinase (ERK)1/2 and p38. These NiCl(2)-induced apoptosis-related signaling responses could be effectively reversed by specific JNK inhibitor SP600125. To the best of our knowledge, this study is the first to show that Ni causes pancreatic β-cell death through a JNK activation-regulated mitochondria-dependent apoptosis-signaling pathway. Crown Copyright © 2011. Published by Elsevier Ireland Ltd. All rights reserved.

Citation

Hsi-Chin Wu, Ching-Yao Yang, Dong-Zong Hung, Chin-Chuan Su, Kuo-Liang Chen, Cheng-Chieh Yen, Tsung-Jung Ho, Yi-Chang Su, Chun-Fa Huang, Chun-Hung Chen, Ling-Mei Tsai, Ya-Wen Chen. Nickel(II) induced JNK activation-regulated mitochondria-dependent apoptotic pathway leading to cultured rat pancreatic β-cell death. Toxicology. 2011 Nov 18;289(2-3):103-11