PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation

• Published in: International journal of molecular sciences 2019-10, Vol.20 (20), p.5084
• Main Authors: Choi, Hoon-In, Park, Jung Sun, Kim, Dong-Hyun, Kim, Chang Seong, Bae, Eun Hui, Ma, Seong Kwon, Kim, Soo Wan
• Format: Article
• Language: English
• Subjects: Binding Sites - genetics; Biopsy; Biosynthesis; Cell Line; Cell lines; Cell Proliferation - genetics; E-cadherin; epithelial-mesenchymal transition (emt); Epithelial-Mesenchymal Transition - genetics; Fibronectin; Fibrosis; Gene expression; Gene Expression Regulation - genetics; Humans; Kidney diseases; Kinases; let-7b/c mirna; Mesenchyme; MicroRNAs - genetics; miRNA; Molecular modelling; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisomes - genetics; pgc-1α; Phosphorylation; Physiology; Protein expression; Proteins; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type II - genetics; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Signal Transduction; Smad protein; Smad Proteins - genetics; Smad2 protein; Snail Family Transcription Factors - genetics; Snail protein; tgf-β/smad signaling; tgfβri; Therapeutic targets; Transcription factors; Transforming Growth Factor beta - genetics; Transforming growth factor-b; Vimentin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20205084

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 (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 , 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 upregulation.