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PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2019 Oct 14; Vol. 20 (20). Date of Electronic Publication: 2019 Oct 14. - Publication Year :
- 2019
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Abstract
- TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-β-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFβRI by PGC-1α was associated with the upregulation of let-7b/c , miRNA for which the 3' untranslated region (UTR) of TGFβRI contains a binding site. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation.
- Subjects :
- Binding Sites genetics
Cell Line
Cell Proliferation genetics
Epithelial-Mesenchymal Transition genetics
Gene Expression Regulation genetics
Humans
Peroxisomes genetics
Receptor, Transforming Growth Factor-beta Type II genetics
Renal Insufficiency, Chronic pathology
Signal Transduction
Smad Proteins genetics
Snail Family Transcription Factors genetics
Transforming Growth Factor beta genetics
MicroRNAs genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics
Receptor, Transforming Growth Factor-beta Type I genetics
Renal Insufficiency, Chronic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 20
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 31614978
- Full Text :
- https://doi.org/10.3390/ijms20205084