Potential molecular mechanism of Guiqi Baizhu Decoction in radiation-induced intestinal edema by regulating HIF-1a, AQP4 and Na+/K+-ATPase

Abstract

Background: Guiqi Baizhu Decoction (GQBZD) has a good protective effect on radiation-induced intestinal edema (RIIE). However, the underlying molecular mechanisms need further elucidation.

Purpose: To reveal the potential mechanism of RIIE and GQBZD treatment.

Methods: SD rats were irradiated with 6Gy X-ray to establish RIIE model. The general condition of the rats was observed; the dry/wet weight ratio of colon tissue was detected; the morphological changes of colon tissue were observed by HE staining; the expressions of ROS, HIF-1α and AQP4 in colon tissue were detected by confocal laser scanning; the expression of edema-related proteins was detected by Western blot. In addition, human colon epithelial cells (NCM460) was irradiated with 2Gy X-ray, and HIF-1α expression in NCM460 was knocked down by small interfering RNA (siRNA) transfection, and the activity of Na⁺/K⁺-ATPase was detected by enzyme activity kit; the ROS expression was detected by flow cytometer; the AQP4 expression was detected by laser confocal microscopy; and the expression of edema-related proteins were detected by Western blot.

Results: We found that after irradiation, the colon tissue of rats was significantly edema, mainly manifested as mucosal and submucosal edema, and the ultrastructure was reflected in the structural damage of nucleus and mitochondria. ROS, HIF-1α and AQP4 were significantly expressed, and Na⁺/K⁺-ATPase expression/activity was decreased. After the intervention of GQBZD, the edema of the colon tissue of the rats was improved, the expressions of ROS, HIF-1α and AQP4 were decreased, and the expression/activity of Na⁺/K⁺-ATPase was increased.

Conclusion: Ionizing radiation (IR) can cause significant intestinal edema. AQP4 and Na⁺/K⁺-ATPase are the key factors of RIIE, which are regulated by ROS and HIF-1α. GQBZD can improve hypoxia and oxidative stress, regulate the expression of AQP4 and Na⁺/K⁺-ATPase, and achieve a protective effect on RIIE. This study is the first to reveal the mechanism of RIIE.

Keywords: AQP4; Guiqi Baizhu decoction; HIF-1α; Na(+)/K(+)-ATPase; Protective effect; Radiation-induced intestinal edema.