NDRG2 ameliorates hepatic fibrosis by inhibiting the TGF-β1/Smad pathway and altering the MMP2/TIMP2 ratio in rats

• Published in: PloS one 2011-11, Vol.6 (11), p.e27710
• Main Authors: Yang, Jiandong, Zheng, Jin, Wu, Lin, Shi, Ming, Zhang, Hongtao, Wang, Xing, Xia, Ning, Wang, Desheng, Liu, Xinping, Yao, Libo, Li, Yan, Dou, Kefeng
• Format: Article
• Language: English
• Subjects: Activation; Adenoviridae - genetics; Animals; Apoptosis; Biochemistry; Biology; Cell cycle; Cell Line; Cell Proliferation - drug effects; Collagen; Damage detection; Dendritic cells; Deposition; Dimethylnitrosamine; Dimethylnitrosamine - pharmacology; Extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - enzymology; Extracellular Matrix - metabolism; Fibrosis; Gelatinase A; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Growth factors; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - enzymology; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatocytes - drug effects; Hepatocytes - enzymology; Hepatocytes - metabolism; Hepatocytes - pathology; Hospitals; Humans; Laboratories; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver - physiopathology; Liver cancer; Liver cirrhosis; Liver Cirrhosis - enzymology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Cirrhosis - physiopathology; Localization; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Medicine; Metalloproteinase; Molecular biology; Myc protein; N-Nitrosodimethylamine; Neurodegeneration; Phosphorylation; Phosphorylation - drug effects; Rats; Retailing; Rodents; Signal Transduction - drug effects; Smad protein; Smad Proteins - metabolism; Smad3 protein; Smooth muscle; Stellate cells; Surgery; Tissue inhibitor of metalloproteinase 2; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Transcription; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027710

Liver fibrosis is a worldwide clinical issue. It has been well established that activated hepatic stellate cells (HSCs) are responsible for excessive extracellular matrix (ECM) deposition in chronically damaged livers. The identification of key elements that control HSCs activation will help to further our understanding of liver fibrosis and improve the outcome of clinical treatment. This study demonstrates that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of liver fibrosis as NDRG2 mRNA and protein levels were reduced during HSCs activation. In addition, enhanced NDRG2 expression reduced Smad3 transcription and phosphorylation, which inhibited HSCs activation by blocking the TGF-β1 signal. Moreover, NDRG2 contributed to an increase in the ratio of matrix metalloproteinase 2 (MMP2) to tissue inhibitor of matrix metalloproteinase 2 (TIMP2), which may facilitate the degradation of the ECM. In dimethylnitrosamine (DMN)-induced fibrotic rat livers, adenovirus-mediated NDRG2 overexpression resulted in decreased ECM deposition and improved liver function compared with controls. In conclusion, the present findings indicate that the modulation of NDRG2 is a promising strategy for the treatment of liver fibrosis.