Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death

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• 作者：Xuezhong Gong ; Vladimir N. Ivanov ; Mercy M. Davidson ; Tom K. Hei
• 关键词：Sodium arsenite ; Tetramethylpyrazine (TMP) ; Nephrotoxicity ; Mitochondrial dysfunction ; Cyclooxygenase ; 2 ; Autophagy
• 刊名：Archives of Toxicology
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：89
• 期：7
• 页码：1057-1070
• 全文大小：4,969 KB
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• 作者单位：Xuezhong Gong (1) (3)
  Vladimir N. Ivanov (1)
  Mercy M. Davidson (2)
  Tom K. Hei (1) (2)
  
  1. Center for Radiological Research, Columbia University, 630 West 168th Street, New York, NY, 10032, USA
  3. Department of Nephrology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai, 200071, China
  2. Department of Radiation Oncology, College of Physician and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA
  
• 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0738

文摘

Although kidney is a target organ of arsenic cytotoxicity, the underlying mechanisms of arsenic-induced nephrotoxicity remain poorly understood. As tetramethylpyrazine (TMP) has recently been found to be a renal protectant in multiple kidney injuries, we hypothesize that TMP could suppress arsenic nephrotoxicity. In this study, human renal proximal tubular epithelial cell line HK-2 was used to elucidate the precise mechanisms of arsenic nephrotoxicity as well as the protective mechanism of TMP in these cells. Sodium arsenite exposure dramatically increased cellular reactive oxygen species (ROS) production, decreased levels of cellular glutathione (GSH), decreased cytochrome c oxidase activity and mitochondrial membrane potential, which indicated mitochondrial dysfunction. On the other hand, sodium arsenite activated pro-inflammatory signals, including β-catenin, nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor alpha and cyclooxygenase-2 (COX-2). Small molecule inhibitors of NF-κB and p38 MAPK blocked arsenic-induced COX-2 expression, suggesting arsenic-induced COX-2 up-regulation was NF-κB- and p38 MAPK-dependent. Finally, sodium arsenite induced autophagy in HK-2 cells at early phase (6?h) and the subsequent apoptosis at 24?h. Treatment by TMP or by the antioxidant N-acetylcysteine decreased arsenic-induced ROS production, enhanced GSH levels, prevented mitochondria dysfunction and suppressed the activation of pro-inflammatory signals and the development of autophagy and apoptosis. Our results suggested that TMP may be used as a new potential therapeutic agent to prevent arsenic-induced nephrotoxicity by suppressing these pathological processes.