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Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and high lethality fibrotic lung disease characterized by excessive fibroblasts proliferation and extracellular matrix accumulation and, ultimately, loss of lung function. Although dysregulation of some miRNAs has been shown to play important roles in the pathophysiological processes of IPF, the role of miRNAs in fibrotic lung diseases is not well understood.
In this study, we found the downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in IPF, which resulted in post-transcriptional derepression of CTGF, and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas over-expression of miR-26a repressed TGF-ß1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-ß1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4 which determines the nuclear translocation of p-Smad2/Smad3.
Taken together, our experiments demonstrated the anti-fibrotic effects for miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of IPF using miR-26a.
The present study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.Molecular Therapy (2014); doi:10.1038/mt.2014.42.
Authors: Liang H, Xu C, Pan Z, Zhang Y, Xu Z, Chen Y, Li T, Li X, Liu Y, Huangfu L, Lu Y, Zhang Z, Yang B, Samuel G, Lu Y, Shan H, Du Z
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