Journal
EXPERIMENTAL CELL RESEARCH
Volume 370, Issue 1, Pages 160-167Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2018.06.016
Keywords
Renal interstitial fibrosis; Peroxisome proliferator-activated receptor; coactivator-1 alpha(PGC-1 alpha); Transforming growth factor-beta 1 (TGF-beta 1)
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Funding
- Kaohsiung Veterans General Hospital Tainan Branch, Taiwan [T001]
- National Science Council, Taiwan [NSC 105-2314-B-273-002]
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Peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha) is a transcriptional coactivator that regulates energy metabolism and mitochondrial biogenesis. Recently, mitochondrial dysfunction has been indicated as an established risk factor for the development of renal fibrosis. However, whether PGC-1 alpha is involved in the pathogenesis of renal fibrosis is unknown. In this study, we treated NRK-49F (normal rat kidney fibroblast) cells with transforming growth factor-beta 1 (TGF-beta 1) for 24 h to establish an in vitro fibrosis model. TGF-beta 1 induced the upregulation of type I collagen, fibronectin, TGF-beta receptor I (TGF beta-RI), TGF beta-RII, Smad4, and pSmad2/3, as well as PGC-1 alpha. NRK-49F cells transfected with pcDNA-PGC-1 alpha showed significantly increased expression of fibronectin and type I collagen, as revealed by western blot assay. Interestingly, transfection with PGC-1 alpha-siRNA caused a stark reversal of TGF-beta 1-induced cellular fibrosis, with concomitant suppression of fibronectin and type I collagen, as revealed by western blot and immunofluorescence assays. Moreover, SB431542 (TGF beta-R1), LY294002 (PI3K/Akt), and SB203580 (p38 MAPK), inhibitors of TGF-beta-associated pathways, markedly suppressed TGF-beta 1-induced PGC-1 alpha upregulation. These results implicate a role of PGC-1 alpha in renal interstitial fibrosis mediated via the TGF beta-RI, PI3K/Akt, and p38 MAPK pathways. Our findings that PGC1 alpha-siRNA downregulates fibronectin and type I collagen suggest that it can be used as a novel molecular treatment for renal fibrosis.
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