Increases in fibrosis-related gene transcripts in livers of dimethylnitrosamine-intoxicated rats.
Fibrosis-related changes in livers of cirrhotic rats induced by dimethylnitrosamine (DMN) have not yet been fully clarified. The aim of this study was to investigate changes in molecular and biochemical markers in DMN-intoxicated rats. DMN was administered to Sprague-Dawley rats for 2 and 5 weeks to induce different degrees of hepatic fibrosis. Liver tissues were assessed for the degree of fibrosis and gene expression. Histological examination of the liver showed a progressive increase in fibrosis scores (1.33 +/- 0.21 and 3.03 +/- 0.29, respectively) and expansion of fibrous septa with collagen-staining fibers in rats after 2 and 5 weeks of DMN administration. Hepatic protein contents of alpha-smooth muscle actin (alpha-SMA) and total collagen were significantly higher in rats administered DMN for both 2 and 5 weeks compared with those in control rats. Hepatic mRNA expressions of alpha-SMA, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor, tissue inhibitor of metalloproteinase-1, and procollagen I and III were increased in DMN rats after 2 and 5 weeks. Abnormal increases in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, plasma and mitochondrial MDA levels, and portal venous pressure were also noted in DMN rats. DMN administration to rats for 2 and 5 weeks induced progressive increases in hepatic fibrosis scores, hepatic mRNA expressions of TGF-beta1 and procollagen I and III genes, plasma levels of ALT and AST, and portal venous pressure, as well as progressive decreases in both liver and body weights. Our results suggest that DMN administration in rats induces biochemical and molecular changes related to fibrogenesis in the liver.
Hsu
Yi-Chao
YC
Institute of Traditional Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
Chiu
Yung-Tsung
YT
Lee
Chang-Yin
CY
Lin
Yun-Lian
YL
Huang
Yi-Tsau
YT
D000199:Actins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D055513:Connective Tissue Growth Factor; D017931:DNA Primers; D004128:Dimethylnitrosamine / Q000633:toxicity*; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
D000199:Actins; C526316:CCN2 protein, rat; D017931:DNA Primers; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011347:Procollagen; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D004128:Dimethylnitrosamine