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Gadolinium promoted proliferation in mouse embryo fibroblast NIH3T3 cells through Rac and PI3K/Akt signaling pathways

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Abstract

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder disease developed in patients with underlying renal insufficiency following exposure to gadolinium-based contrast agents (GBCAs). Previous studies have demonstrated that GdCl3 can promote NIH3T3 fibroblast cell proliferation, which provide a new clue to the role of GBCAs in the development of NSF. In the present study, we further clarify the molecular mechanism of Gd-promoted proliferation. The results showed that intervention with the Rac inhibitor NSC23766 abrogated Gd-promoted proliferation. The levels of active Rac1 significantly increased in Gd-treated cells detected by pull-down assays. In addition, the phosphorylation of Akt was significantly elevated in the treatment group, which was blocked by NSC23766. NSC23766 also reduced the migration of NIH3T3 cells enhanced by Gd. Moreover, the F-actin cytoskeleton was strengthened and the mitotic cell numbers was significantly increased after exposure to Gd. These results suggest that Rac and PI3K/Akt signaling pathways, as well as integrin-mediated signal pathway may play important roles in Gd-induced cell proliferation. In addition, under serum-free condition, Gd could decrease ROS accumulation and increase NIH3T3 cell survival.

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Abbreviations

DCFH-DA:

2′,7′-dichlorofluorescein diacetate

DMEM:

Dulbecco’s Modified Eagle’s Medium

ERK:

Extracellular signal-regulated kinase

FBS:

Fetal bovine serum

Gd:

Gadolinium

GBCAs:

Gadolinium-based contrast agents

GC:

Gadolinium chelates

GdCl3 :

Gadolinium chloride

NSF:

Nephrogenic systemic fibrosis

PBS:

Phosphate-buffered saline

PI3K:

Phosphatidylinositol 3-kinase

Rac1:

Ras-related C3 botulinum toxin substrate 1

ROS:

Reactive oxygen species

SSc:

Systemic sclerosis

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Acknowledgments

This work was supported financially by the National Natural Science Foundation of China (No. 21271131).

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Authors and Affiliations

  1. College of Life Science, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, 518060, People’s Republic of China

    Liming Shen, Aochu Yang, Cheng Chen, Cuiping Mo, Youjiao Chen & Qiong Liu

  2. School of Public Health, Guiyang Medical University, Guiyang, 550004, People’s Republic of China

    Pengwei Yao, Xiaohong Sun & Lei Shi

Authors
  1. Liming Shen
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  2. Aochu Yang
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  3. Pengwei Yao
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  4. Xiaohong Sun
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  5. Cheng Chen
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  6. Cuiping Mo
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  7. Lei Shi
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  8. Youjiao Chen
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  9. Qiong Liu
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Correspondence to Qiong Liu.

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Shen, L., Yang, A., Yao, P. et al. Gadolinium promoted proliferation in mouse embryo fibroblast NIH3T3 cells through Rac and PI3K/Akt signaling pathways. Biometals 27, 753–762 (2014). https://doi.org/10.1007/s10534-014-9769-9

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  • DOI: https://doi.org/10.1007/s10534-014-9769-9

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