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Imidazoline I2 receptor inhibitor idazoxan regulates the progression of hepatic fibrosis via Akt-Nrf2-Smad2/3 signaling pathway.

ABSTRACT: Liver fibrosis is a global health problem and its relationship with imidazoline I2 receptor has not been reported. This study aimed to investigate the effects and underlying mechanisms of imidazoline I2 receptor (I2R) inhibitor idazoxan (IDA) on carbon tetrachloride (CCl4)-induced liver fibrosis. In vivo liver fibrosis in mice was induced by intraperitoneally injections of CCl4 for eight weeks, and in vitro studies were performed on activated LX2 cells treated with transforming growth factor-? (TGF-?). Our results showed that IDA significantly improved liver inflammation, ameliorated hepatic stellate cells activation and reduced collagen accumulation by suppressing the pro-fibrogenic signaling of TGF-?/Smad. Further investigation showed that IDA significantly balanced oxidative stress through improving the expressions and activities of anti-oxidant and detoxifying enzymes and activating Nrf2-the key defender against oxidative stress with anti-fibrotic potentials. Even more impressively, knock out of Nrf2 or suppression of Akt by perifosine (PE) eliminated the anti-oxidant and anti-fibrotic effects of IDA in vivo and in vitro, suggesting that Akt/Nrf2 constitutes a critical component of IDA's protective functions. Taken together, IDA exhibits potent effects against liver fibrosis via Akt-Nrf2-Smad2/3 signaling pathway, which suggests that specifically targeting I2R may be a potentially useful therapeutic strategy for liver fibrosis.

SUBMITTER: Xuanfei L

PROVIDER: S-EPMC5400562 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Imidazoline I2 receptor inhibitor idazoxan regulates the progression of hepatic fibrosis via Akt-Nrf2-Smad2/3 signaling pathway.

Xuanfei Li L Hao Chen C Zhujun Yi Y Yanming Liu L Jianping Gong G

Oncotarget 20170301 13

Liver fibrosis is a global health problem and its relationship with imidazoline I2 receptor has not been reported. This study aimed to investigate the effects and underlying mechanisms of imidazoline I2 receptor (I2R) inhibitor idazoxan (IDA) on carbon tetrachloride (CCl4)-induced liver fibrosis. In vivo liver fibrosis in mice was induced by intraperitoneally injections of CCl4 for eight weeks, and in vitro studies were performed on activated LX2 cells treated with transforming growth factor-β ( ...[more]

PMID: 28423499

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Project description:AIM:To investigate the effects of blueberry on hepatic fibrosis and NF-E2-related factor 2 (Nrf2) transcription factor in rats. METHODS:Forty-five male Sprague-Dawley rats were randomly divided into control group (A); CCl(4)-induced hepatic fibrosis group (B); blueberry prevention group (C); Dan-shao-hua-xian capsule (DSHX) prevention group (D); and blueberry + DSHX prevention group (E). Liver fibrosis was induced in rats by subcutaneous injection of CCl(4) and a high-lipid/low-protein diet for 8 wk (except the control group). The level of hyaluronic acid (HA) and alanine aminotransferase (ALT) in serum was examined. The activity of superoxide dismutase (SOD), glutathione-S-transferase (GST) and malondialdehyde (MDA) in liver homogenates was determined. The degree of hepatic fibrosis was evaluated by hematoxylin and eosin and Masson staining. Expression of Nrf2 and NADPH quinone oxidoreductase 1 (Nqo1) was detected by real-time reversed transcribed-polymerase chain reaction, immunohistochemical techniques, and western blotting. RESULTS:Compared with group B, liver indices, levels of serum HA and ALT of groups C, D and E were reduced (liver indices: 0.038 +/- 0.008, 0.036 +/- 0.007, 0.036 +/- 0.005 vs 0.054 +/- 0.009, P < 0.05; HA: 502.33 +/- 110.57 ng/mL, 524.25 +/- 255.42 ng/mL, 499.25 +/- 198.10 ng/mL vs 828.50 +/- 237.83 ng/mL, P < 0.05; ALT: 149.44 +/- 16.51 U/L, 136.88 +/- 10.07 U/L, 127.38 +/- 11.03 U/L vs 203.25 +/- 31.62 U/L, P < 0.05), and SOD level was significantly higher, but MDA level was lower, in liver homogenates (SOD: 1.36 +/- 0.09 U/mg, 1.42 +/- 0.13 U/mg, 1.50 +/- 0.15 U/mg vs 1.08 +/- 0.19 U/mg, P < 0.05; MDA: 0.294 +/- 0.026 nmol/mg, 0.285 +/- 0.025 nmol/mg, 0.284 +/- 0.028 nmol/mg vs 0.335 +/- 0.056 nmol/mg, P < 0.05). Meanwhile, the stage of hepatic fibrosis was significantly weakened (P < 0.05). Compared with group A, the activity of GST liver homogenates and expression levels of Nrf2 and Nqo1 in group B were elevated (P < 0.05). The expression level of Nrf2 and Nqo1 in groups C, D, and E were increased as compared with group B, but the difference was not significant. CONCLUSION:Blueberry has preventive and protective effects on CCl(4)-induced hepatic fibrosis by reducing hepatocyte injury and lipid peroxidation. However, these effects may not be related to the activation of Nrf2 during long-term of CCl(4).

Dataset Information

Imidazoline I2 receptor inhibitor idazoxan regulates the progression of hepatic fibrosis via Akt-Nrf2-Smad2/3 signaling pathway.

Publications

Imidazoline I2 receptor inhibitor idazoxan regulates the progression of hepatic fibrosis via Akt-Nrf2-Smad2/3 signaling pathway.

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