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