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      The role of unfolded protein response and ER-phagy in quantum dots-induced nephrotoxicity: an in vitro and in vivo study.

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          Abstract

          Unfolded protein response (UPR) and endoplasmic reticulum (ER)-phagy are essential for cell homeostasis. Quantum dots (QDs), which have been widely used for biomedical applications, can accumulate in the kidney tissues and may cause renal dysfunction. However, the molecular mechanism of QDs-induced nephrotoxicity is still obscure. The present study was aimed to elucidate the role and mechanism of UPR and ER-phagy in QDs-induced nephrotoxicity. Herein, human embyronic kidney (HEK) cells were exposed to 15, 30, 45, and 60 nM cadmium telluride (CdTe)-QDs for 12 and 24 h. And CdTe-QDs (30-60 nM) inhibited the HEK cell viability. The clathrin-dependent endocytosis was determined as the main pathway of CdTe-QDs cellular uptake. Within cells, CdTe-QDs disrupted ER ultrastructure and induced UPR and FAM134B-dependent ER-phagy. Blocking UPR with inhibitors or siRNA rescued the FAM134B-dependent ER-phagy, which was triggered by CdTe-QDs. Moreover, suppression of UPR or FAM134B-dependent ER-phagy restored the cell vability. In vivo, mice were intravenously injected with 8 and 16 nmol/kg body weight CdTe-QDs for 24 h. Kidney was shown as one of highest distributed organs of CdTe-QDs, resulting in renal dysfunction, as well as UPR and FAM134B-dependent ER-phagy in it. Thus, for the first time, we demonstrated that ER-phagy can be triggered by nanomaterials both in vitro and in vivo. In addition, blocking of UPR and ER-phagy showed protective effects against CdTe-QDs-induced toxicity in kideny cells. Notably, a secreted alkaline phosphatase reporter gene system has been developed as a sensitive and rapid method for evaluating the ER quality under the exposure of nanomaterials.

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          Author and article information

          Journal
          Arch. Toxicol.
          Archives of toxicology
          Springer Science and Business Media LLC
          1432-0738
          0340-5761
          Apr 2018
          : 92
          : 4
          Affiliations
          [1 ] State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, People's Republic of China.
          [2 ] Research Institute for Biomimetics and Soft Matter, Xiamen University, Xiamen, 361005, People's Republic of China.
          [3 ] Research Institute for Biomimetics and Soft Matter, Xiamen University, Xiamen, 361005, People's Republic of China. phyliuxy@nus.edu.sg.
          [4 ] Department of Physics, National University of Singapore, 2 Science Drive 3, Singapore, 117542, Singapore. phyliuxy@nus.edu.sg.
          [5 ] State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, People's Republic of China. linzhn@xmu.edu.cn.
          [6 ] State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, 361102, People's Republic of China. hecy@xmu.edu.cn.
          Article
          10.1007/s00204-018-2169-0
          10.1007/s00204-018-2169-0
          29435600
          50a0c264-c4df-4003-b096-1acbf2668ad6
          History

          Autophagy,ER-phagy,Endoplasmic reticulum quality control,FAM134B,Kidney,Quantum dots,Unfolded protein response

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