【Abstract】Objective To explore the potential link between liver injury caused by high-altitude hypoxic environment and nuclear factor E2-related factor 2 (NRF2) in rats. Methods Wistar rat model of hypoxic liver injury was constructed in a plateau simulation chamber (simulated altitude of 6 000 m). The expression of NRF2 was regulated by intraperitoneal injection of the NRF2-specific agonist-tert-butyl hydroquinone (TBHQ), 30 mg/(kg·d). The subjected Wistar rats were then divided into a control group (normoxic condition), high-altitude/hypoxia (HH) group, and hypoxia combined with TBHQ treatment (HH+TBHQ) group. HE staining and liver index were used to assess the pathological structural changes in rat liver. ELISA was employed to determine the oxidative stress and antioxidant capacity (MDA/SOD) in rat peripheral blood and liver tissues. The generation of reactive oxygen species (ROS) in the liver tissues was assessed by DHE probe, and cell apoptosis in the liver was detected by TUNEL staining. The mRNA and protein levels of NRF2 were determined by RT-qPCR and Western blotting, respectively. GraphPad Prism 8.0.1 was applied for statistical analysis. Intergroup comparison was performed using t test or one-way analysis of variance depending on data type. Results Compared with the control group, the HH group had significantly higher liver index (P<0.001), damaged liver tissue observed by HE staining, elevated liver ALT (P<0.001) and AST (P<0.05) contents, as well as ROS level (P<0.001), enhanced lipid peroxidation (P<0.05) but declined antioxidant capacity in both serum and liver tissues (P<0.05). TBHQ treatment resulted in obvious increases in both mRNA and protein expression of NRF2 in the liver tissues (P<0.001), decreased liver index (P<0.05), alleviation of structural damage in liver cells, decreases in serum ALT (P<0.01) and AST (P<0.01) levels, reduced ROS level (P<0.01), declined lipid peroxidation (P<0.01) but enhanced antioxidant capacity in both serum and liver tissues (P<0.05), when compared with the rats in the HH group. TUNEL staining indicated that the apoptosis in liver cells was significantly increased in the HH group than the control group (P<0.01), and the apoptotic level was notably decreased in the HH+TBHQ group (P<0.01). Conclusion Exposure to high-altitude hypoxic condition causes liver injury and declined liver function, which is accompanied by increases in NRF2 level and cell apoptosis. However, up-regulation of NRF2 can alleviate liver injury by reducing hepatocytic apoptosis.

This work was supported by the National Key Research and Development Program of China (2020YFC1512301).