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-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.