Imidazoline I(2) receptor inhibitor idazoxan regulates the progression of hepatic fibrosis via Akt-Nrf2-Smad2/3 signaling pathway

Liver fibrosis is a global health problem and its relationship with imidazoline I(2) receptor has not been reported. This study aimed to investigate the effects and underlying mechanisms of imidazoline I(2) receptor (I(2)R) inhibitor idazoxan (IDA) on carbon tetrachloride (CCl(4))-induced liver fibrosis. In vivo liver fibrosis in mice was induced by intraperitoneally injections of CCl(4) 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 I(2)R may be a potentially useful therapeutic strategy for liver fibrosis.