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Exp Cell Res ; 370(1): 160-167, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29913155

ABSTRACT

Peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1α) 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-1α 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-ß1) for 24 h to establish an in vitro fibrosis model. TGF-ß1 induced the upregulation of type I collagen, fibronectin, TGF-ß receptor I (TGFß-RI), TGFß-RII, Smad4, and pSmad2/3, as well as PGC-1α. NRK-49F cells transfected with pcDNA-PGC-1α showed significantly increased expression of fibronectin and type I collagen, as revealed by western blot assay. Interestingly, transfection with PGC-1α-siRNA caused a stark reversal of TGF-ß1-induced cellular fibrosis, with concomitant suppression of fibronectin and type I collagen, as revealed by western blot and immunofluorescence assays. Moreover, SB431542 (TGFß-RI), LY294002 (PI3K/Akt), and SB203580 (p38 MAPK), inhibitors of TGF-ß-associated pathways, markedly suppressed TGF-ß1-induced PGC-1α upregulation. These results implicate a role of PGC-1α in renal interstitial fibrosis mediated via the TGFß-RI, PI3K/Akt, and p38 MAPK pathways. Our findings that PGC-1α-siRNA downregulates fibronectin and type I collagen suggest that it can be used as a novel molecular treatment for renal fibrosis.


Subject(s)
Antifibrinolytic Agents/pharmacology , Fibrosis/drug therapy , Kidney Diseases/drug therapy , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , RNA, Small Interfering/pharmacology , Transforming Growth Factor beta1/metabolism , Animals , Cell Line , Collagen Type I/metabolism , Disease Models, Animal , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibronectins/metabolism , Fibrosis/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney Diseases/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Rats , Transfection/methods , Up-Regulation/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism
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