Rabeprazole attenuates fibrosis by modulating SMAD3 linker region phosphorylation
Abstract
However, the possible role of rabeprazole in fibrosis remains unclear. Western blotting and reverse transcription-quantitative PCR were used to analyze gene expression at mRNA and protein levels. In addition, immunofluorescence, immunoprecipitation (IP) and dual luciferase reporter assays were performed to identify the mechanism underlying rabeprazole-modulated fibrosis. Plasmid transfection was conducted to rescue the experiments. In the present study, EMT inhibition was observed in gastric epithelial cells, including AGS and GES-1 cells, in response to rabeprazole treatment. Specifically, stimulation with rabeprazole 100 µM caused an upregulation of transcriptional intermediary factor 1γ (TIF1γ) expression, leading to a decrease in fibronectin (FN) and collagen type I alpha 1 chain (Col1a1) expression, whereas no significant variation was observed in the expression of α-smooth muscle actin expression. Moreover, depletion of TIF1γ expression largely blocked the influence of rabeprazole on Col1a1 and FN expression. Mechanistically, the IP analysis showed that endogenous SMAD family member 3 (SMAD3) interacted with TIF1γ, and this interaction was enhanced in response to rabeprazole, which further inhibited SMAD3 linker phosphorylation and nuclear translocation as evidenced through subcellular fractionation experiments. Overall, the present findings reveal a previously unrecognized antifibrotic activity of rabeprazole. These findings enriched the biological function of…
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