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

Toxicokinetics and Metabolism
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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.

Keywords

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

Abbreviations

4-PBA

4-phenylbutyrate

BUN

Blood urea nitrogen

CCK8

Cell counting kit 8

CdTe

Cadmium telluride

CeO2

Ceric oxide

Chlor

Chlorpromazine

CQ

Chloroquine

CREA

Creatinine

CytoD

Cytochalasin D

DAPI

4′,6-diamidino-2-phenylindole

DAB

Diaminobenzidine

eIF2α

Eukaryotic initiation factor 2 α-subunit

ER

Endoplasmic reticulum

ERAD

ER-associated protein degradation

ERQC

ER quality control

FAM134

The reticulon family with sequence similarity 134

Fluc

Firefly luciferase

GABARAP

γ-aminobutyric acid receptor-associated protein

GRP78

Glucose-regulated protein 78

HE

Hematoxylin and eosin

HRTEM

High-resolution transmission electron microscopy

LC3

Microtubules-associated protein 1-light chain 3

LDH

Lactate dehydrogenase

MPA

Mercaptopropionic acid

MT

Metallothionein

MTS

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

NaHTe

Sodium hydrogen tellurium

NaBH4

Sodium borohydride

NPs

Nanoparticles

OD

Optical density

PERK

PKR-like endoplasmic reticulum kinase

QDs

Quantum dots

qRT-PCR

Quantitative real-time PCR

SEAP

Secreted alkaline phosphatase

SiO2

Silica

TEM

Transmission electron microscopy

Tg

Thapsigargin

TiO2

Titanium dioxide

TUDCA

Tauroursodeoxycholic acid

UA

Uric acid

UPR

Unfolded protein response

ZnO

Zinc oxide

Notes

Acknowledgements

We appreciate Dr. Lei Guo and Dr. Si Chen (National Center for Toxicological Research, USA) for their kind gift of plasmids related to SEAP reporter system. We appreciate Chao Song (Freshwater Fisheries Research Centre of Chinese Academy of Fishery Sciences) for help with AAS technique. We are grateful to Dr. Vitali Stanevich (R&D department, Janssen, USA), and Dr. Feng Guo (University of Wisconsin, USA) for editing the language. This work was supported by grants from the National Natural Science Foundation of China (NSFC Nos. 81402648, 81573181, 81472997, 81773465), the Natural Science Foundation of Fujian Province of China (No. 2015J01344), the Scientific Research Foundation of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (No. 2016ZY003), and the 1000 Talents Program from Xiamen University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

204_2018_2169_MOESM1_ESM.doc (555 kb)
Supplementary material 1 (DOC 555 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shengwei Jiang
    • 1
  • Yuchun Lin
    • 1
  • Huan Yao
    • 1
  • Chuanli Yang
    • 1
  • Liyin Zhang
    • 1
  • Bing Luo
    • 1
  • Zhao Lei
    • 1
  • Liwei Cao
    • 2
  • Naibo Lin
    • 2
  • Xiangyang Liu
    • 2
    • 3
  • Zhongning Lin
    • 1
  • Chengyong He
    • 1
  1. 1.State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenPeople’s Republic of China
  2. 2.Research Institute for Biomimetics and Soft MatterXiamen UniversityXiamenPeople’s Republic of China
  3. 3.Department of PhysicsNational University of SingaporeSingaporeSingapore

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