Gadolinium Chloride Promotes Proliferation of HEK293 Human Embryonic Kidney Cells by Activating EGFR/PI3K/Akt and MAPK Pathways
BioMetals(2019)
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 (Gd 3+ ) concentration- and time-dependently promoted the proliferation of HEK293 human embryonic kidney cells by increasing DNA synthesis. Gd 3+ 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, Gd 3+ activated EGFR signaling possibly by enhancing EGFR clustering on the cell membrane. Inhibition of EGFR by gefitinib blocked Gd 3+ -induced proliferation. Gd 3+ 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 Gd 3+ in the pathogenesis of nephrogenic systemic fibrosis, and suggests the inhibition of EGFR/Akt/ERK signaling as a potential treatment strategy.
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Key words
Gadolinium,Nephrogenic systemic fibrosis,Cell proliferation,Epidermal growth factor receptor,Mitogen-activated protein kinases
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