Smad3 Specific Inhibitor, Naringenin, Decreases the Expression of Extracellular Matrix Induced by TGF-β1 in Cultured Rat Hepatic Stellate Cells

• DOI: 10.1007/s11095-005-9043-5
• Publication Date: 2005-12-08T01:37:50Z
• Authors: Xingjun Liu; Wei Wang; Han Hu; Ning Tang; Chunling Zhang; Wei Liang; Minwei Wang
• Keywords: 0301 basic medicine; Cell Survival; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Estrogen Antagonists; Collagen Type I; Extracellular Matrix; Fibronectins; Rats; 3. Good health; Transforming Growth Factor beta1; 03 medical and health sciences; Gene Expression Regulation; Liver; Transforming Growth Factor beta; Flavanones; Plasminogen Activator Inhibitor 1; Animals; RNA; RNA, Messenger; Smad3 Protein; Phosphorylation; Cells, Cultured

During the process of liver fibrogenesis, transforming growth factor-beta (TGF-beta) plays an essential role in modulating extracellular matrix (ECM) gene expression, and a growing body of evidence suggests that this is a Smad3-dependent process in the activated hepatic stellate cells (HSCs). Naringenin showed a significantly protective effect on experimental rat liver fibrosis, in our efforts to elucidate its antifibrosis molecular mechanisms and to find a novel target based on Smad3 signaling for challenging fibrosis diseases.In this study, reverse transcription-polymerase chain reaction and Western blot assays were used to investigate the inhibitory effect of naringenin on ECM formation induced by TGF-beta1 in the HSC-T6 cells.Naringenin reduced not only the accumulation of ECM, including collagen Ialpha1 (Col Ialpha1), fibronectin (FN), and plasminogen activator inhibitor-1 (PAI-1), but also the production of Smad3 induced by TGF-beta1 in both mRNA and protein levels in a dose-dependent manner. Moreover, naringenin selectively inhibited the transcription of Smad3, but not other Smads involved in TGF-beta1 signaling pathways.Our data demonstrate that naringenin can exert antifibrogenic effects by directly or indirectly down-regulating Smad3 protein expression and phosphorylation through TGF-beta signaling.