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Open AccessArticle

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

Department of Internal Medicine, Chonnam National University Medical School, 42 Jebongro, Gwangju 61469, Korea
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Int. J. Mol. Sci. 2019, 20(20), 5084; https://doi.org/10.3390/ijms20205084
Received: 2 September 2019 / Revised: 4 October 2019 / Accepted: 10 October 2019 / Published: 14 October 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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. View Full-Text
Keywords: PGC-1α; let-7b/c miRNA; TGFβRI; TGF-β/Smad signaling; epithelial-mesenchymal transition (EMT) PGC-1α; let-7b/c miRNA; TGFβRI; TGF-β/Smad signaling; epithelial-mesenchymal transition (EMT)
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Choi, H.-I.; Park, J.S.; Kim, D.-H.; Kim, C.S.; Bae, E.H.; Ma, S.K.; Kim, S.W. PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation. Int. J. Mol. Sci. 2019, 20, 5084.

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