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.
Highlights
Renal fibrosis is a central event in the progression of chronic kidney diseases (CKDs) that leads to end-stage kidney diseases [1]
The expression of E-cadherin, which is characteristic of epithelial cells, was reduced in the ureteral obstruction (UUO) kidney and accumulation of extracellular matrix protein (Col1a1 and Col3a1) was increased in the UUO kidney (Figure 1A and Figure S1)
Consistent with the reduction in PGC-1α in UUO kidneys, the protein expression of PGC-1α in HK-2 cells was lowest at the same time when the transforming growth factor-β (TGF-β)-induced fibrotic progression peaked after one day (Figure 2A,B)
Summary
Renal fibrosis is a central event in the progression of chronic kidney diseases (CKDs) that leads to end-stage kidney diseases [1]. Among multiple mediators, transforming growth factor-β (TGF-β) is a key mediator that triggers activation of progressive renal fibrosis signaling pathways [1,2]. These pleiotropic effects of TGF-β are mediated via three types of TGF-β receptors (TGFβRI, TGFβRII and TGFβRIII) that function as serine-threonine kinases. In a Smad-dependent pathway, TGF-β binds to TGFβRII, which binds and phosphorylates TGFβRI. These events trigger the recruitment of the receptor-regulated Smad proteins (R-Smads) Smad and Smad to the cytoplasmic domain of activated TGFβRI, which phosphorylates Smad2/3. Targeting TGF-β/Smad signaling remains an attractive target for the development of therapeutics for fibrotic progression [4]
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