Indeed, the expression of PGC-1α in the kidney overlaps in the proximal tubule and medullary thick ascending limb of Henle, where mitochondrial activity is high. Mitochondria are a major energy source for cells, and the kidney requires a constant level of ATP to transport solutes along nephrons. PGC-1α is a master regulator of mitochondrial biogenesis. Targeting TGF-β/Smad signaling remains an attractive target for the development of therapeutics for fibrotic progression. Once phosphorylated, Smad2/3 form a trimer with Smad4, which is then translocated to the nucleus where it binds to Smad-binding elements to modulate target genes.

These events trigger the recruitment of the receptor-regulated Smad proteins (R-Smads) Smad2 and Smad3 to the cytoplasmic domain of activated TGFβRI, which then phosphorylates Smad2/3. In a Smad-dependent pathway, TGF-β binds to TGFβRII, which binds and phosphorylates TGFβRI. 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. Among multiple mediators, transforming growth factor-β (TGF-β) is a key mediator that triggers activation of progressive renal fibrosis signaling pathways. Renal fibrosis is a central event in the progression of chronic kidney diseases (CKDs) that leads to end-stage kidney diseases. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation. 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. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α 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. 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). 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). 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.

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