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Gadolinium promoted proliferation in mouse embryo fibroblast NIH3T3 cells through Rac and PI3K/Akt signaling pathways
Liming Shen1, Aochu Yang, Pengwei Yao
1College of Life Science, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, 518060, People's Republic of China.
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.
Insights
Gadolinium-based contrast agents (GBCAs) can cause Nephrogenic Systemic Fibrosis (NSF). This study reveals that Gd promotes fibroblast proliferation via Rac1 and PI3K/Akt pathways, offering insights into NSF development.
Area of Science:
- Cell Biology
- Toxicology
- Biochemistry
Background:
- Nephrogenic Systemic Fibrosis (NSF) is a fibrotic disease linked to gadolinium-based contrast agents (GBCAs) in patients with kidney insufficiency.
- Previous research indicated that GdCl3 promotes fibroblast proliferation, suggesting a role for GBCAs in NSF pathogenesis.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying gadolinium (Gd)-induced fibroblast proliferation.
- To investigate the involvement of specific signaling pathways in Gd-promoted cell growth and migration.
Main Methods:
- Utilized NIH3T3 fibroblast cell models.
- Employed Rac inhibitor (NSC23766) to block Gd-induced proliferation.
- Assessed active Rac1 levels using pull-down assays.
- Measured Akt phosphorylation via Western blotting.
- Analyzed F-actin cytoskeleton organization and mitotic cell counts.
- Evaluated cell migration and reactive oxygen species (ROS) accumulation.
Main Results:
- Gd exposure significantly enhanced NIH3T3 fibroblast proliferation and migration.
- Inhibition of Rac1 with NSC23766 abrogated Gd-promoted proliferation and migration.
- Active Rac1 levels and Akt phosphorylation were elevated in Gd-treated cells, effects blocked by NSC23766.
- Gd treatment strengthened the F-actin cytoskeleton and increased mitotic cell numbers.
- Gd reduced ROS accumulation and enhanced cell survival under serum-free conditions.
Conclusions:
- Gadolinium promotes fibroblast proliferation and migration through the activation of Rac1 and PI3K/Akt signaling pathways.
- Integrin-mediated signaling may also contribute to Gd-induced cell proliferation.
- These findings provide crucial molecular insights into the pathogenesis of NSF and the role of GBCAs.
