Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS- and mitochondria-mediated pathway

• Published in: Toxicology and applied pharmacology Vol. 259; no. 2; pp. 177 - 186
• Main Authors: Wang, Yi-Fen, Shyu, Huey-Wen, Chang, Yi-Chuang, Tseng, Wei-Chang, Huang, Yeou-Lih, Lin, Kuan-Hua, Chou, Miao-Chen, Liu, Heng-Ling, Chen, Chang-Yu
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.03.2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; ACETATES; Acetates - antagonists & inhibitors; Acetates - toxicity; acetylcysteine; Acetylcysteine - pharmacology; APOPTOSIS; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; carcinogenicity; CARCINOGENS; caspases; Caspases - metabolism; Cell Line; Cell Survival - drug effects; Comet Assay; cytochrome c; Cytotoxicity; DNA Damage; DNA DAMAGES; Flow Cytometry; HK-2 cells; Humans; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; kidneys; LUNGS; Medical sciences; membrane potential; Membrane Potential, Mitochondrial - physiology; MITOCHONDRIA; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial membrane; NICKEL; Nickel (II); Organometallic Compounds - antagonists & inhibitors; Organometallic Compounds - toxicity; protein synthesis; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; signal transduction; TOXICITY; Toxicology; TUBULES; Cytotoxicity; Reactive oxygen species; Mitochondria; Nickel (II); HK-2 cells; Apoptosis; Human; Proximal; Oxidative stress; Nickel II; In vitro; Kidney; Renal tubule; Urinary system; Cell death
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2011.12.022

Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II)-induced renal cytotoxicity.