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논문분류	춘계학술대회 초록집
제목	PGC-1alpha protects TGF-β induced fibrosis by suppressing let7c-mediated TGFβRI expression
저자	Hoon-In Choi, Dong-Hyun Kim, Jung Sun Park, Eun Hui Bae, Seong Kwon Ma, Soo Wan Kim
출판정보	2018; 2018(1):
키워드	PGC-1α \| TGF-β \| TGFβRI \| let-7c
초록	Objectives: TGF-β (transforming growth factor-β) is known as a central mediator in renal fibrosis. Recently, TGF-β decreases a microRNA let-7c and this is associated with increased expression of let-7c targets, including TGFβ receptor type 1 (TGFβRI). The peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a master player that regulates mitochondrial biogenesis and the antioxidant response. However, the physiological effects of PGC-1α in renal fibrosis have not been fully characterized and the underlying mechanisms remain poorly understood. Methods: Human proximal tubule (HK-2) cells were stable transduced with human PGC-1α expression vector (PGC-1αO/E) or empty vector (PGC-1αMock) containing zeocin selective marker and were treated with TGF-β for the indicated time. The change of gene expression (fibrotic markers, TGFβRI, TGFβRII, and let-7c) and activation of signal molecules (phosphor form of Smad2/3) in TGF-β treated both PGC-1αMock and PGC-1αO/E cells were compared by western blotting, real-time PCR, immunofluorescence. Results: Consistent with down-regulation of PGC-1α in fibrotic progression of UUO-induced kidney, the mRNA level and protein level of PGC-1α also were reduced in TGF-β treated HK-2 cells. Stable expression of hPGC-1α in HK-2 cells (PGC-1αO/E) attenuated the TGF-β induced upregulation of fibrotic markers (fibronectin, vimentin, and α-SMA) and downregulation of epithelial marker (E-cadherin), compared to PGC-1αMock. Overexpression of PGC-1α significantly was delayed phosphorylation of Smad2/3. PGC-1αO/E cells were specifically down-regulated in mRNA and protein level of TGFβRI, but not TGFβRII. We identified that let-7c was regulated by PGC-1α-specific manner and anti-fibrotic effects in PGC-1αO/E cells was resulted by down-regulation of TGFβRI mediated by upregulation of let-7c. Conclusions: PGC-1α regulates canonical TGF-β/Smad2/3 signal pathway by targeting let-7- mediated TGFβRI expression, resulting in anti-fibrotic effect.
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