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-β (TGF-β). 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-β/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.
Highlights
Liver fibrosis and cirrhosis occur as a result of liver disease including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis [1,2,3]
To further explore the effects of IDA on CCl4-induced liver fibrosis mice, we examined the levels of liver enzymes in serum
The results showed that CCl4-induced a significant increase in serum ALT, AST, total bilirubin (TB), total cholesterol (TC) and triglycerides (TG) and a remarkable decrease in serum albumin (Alb), as compared to control group
Summary
Liver fibrosis and cirrhosis occur as a result of liver disease including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis [1,2,3]. In response to liver damage, the quiescent HSCs are activated and differentiated into fibrogenic myofibroblast-like cells, which express many ECM proteins including collagen type-I, α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), matrix metalloproteinase (MMP), and tissue inhibitors of metalloproteinase, which contributes to liver fibrosis [7]. Among these proteins, TGF-β is considered to be the most important one which mediates HSC trans-differentiation through the canonical TGF-β/Smad signaling pathway. The p-Smad2/3 form complexes with Smad and translocate to the nucleus to regulate the transcription of down-stream pro-fibrogenic genes [8]
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