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BioMetals

, Volume 32, Issue 4, pp 683–693 | Cite as

Gadolinium chloride promotes proliferation of HEK293 human embryonic kidney cells by activating EGFR/PI3K/Akt and MAPK pathways

  • Xin Pan
  • Jinxia Li
  • Xia He
  • Jianjun Deng
  • Faqin Dong
  • Kui Wang
  • Siwang YuEmail author
Article
  • 33 Downloads

Abstract

Prolonged exposure to gadolinium-based contrast agents has been reported to trigger nephrogenic systemic fibrosis in end stage renal disease patients. However, the exact molecular mechanisms are not fully understood, and no effective therapy is available to date. In the present study, we report that gadolinium chloride (Gd3+) concentration- and time-dependently promoted the proliferation of HEK293 human embryonic kidney cells by increasing DNA synthesis. Gd3+ treatment increased the protein levels of phosphorylated Akt and MAPKs. Inhibition of Akt and ERK by pharmacological inhibitors abolished the increased proliferation and cell cycle progression. Furthermore, Gd3+ activated EGFR signaling possibly by enhancing EGFR clustering on the cell membrane. Inhibition of EGFR by gefitinib blocked Gd3+-induced proliferation. Gd3+ exposure also upregulated the mRNA levels of TGFβ-1, TGFβR1, TNFα, TIMP-1 and integrin αV, β1 which could also be attenuated by the inhibition of Akt and ERK signaling. Our study provides new clues for the etiological role of Gd3+ in the pathogenesis of nephrogenic systemic fibrosis, and suggests the inhibition of EGFR/Akt/ERK signaling as a potential treatment strategy.

Keywords

Gadolinium Nephrogenic systemic fibrosis Cell proliferation Epidermal growth factor receptor Mitogen-activated protein kinases 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21001011, 81472657) and the state key laboratory of environmental chemistry and ecotoxicology (KF2013-17). The authors thank the member of Yu’s group for their helpful discussions and suggestions.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Xin Pan
    • 1
  • Jinxia Li
    • 2
  • Xia He
    • 1
  • Jianjun Deng
    • 3
  • Faqin Dong
    • 3
  • Kui Wang
    • 1
  • Siwang Yu
    • 1
    Email author
  1. 1.State Key Laboratory of Natural and Biomimetic DrugsPeking University School of Pharmaceutical SciencesBeijingPeople’s Republic of China
  2. 2.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy PhysicsChinese Academy of Sciences (CAS)BeijingPeople’s Republic of China
  3. 3.Key Lab of Solid Waste Treatment and Resource, Ministry of Education/School of Environment and ResourceSouthwest University of Science and TechnologyMianyangPeople’s Republic of China

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