Department of Urology, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
Department of Urology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
J Biochem Mol Toxicol. 2024 Aug;38(8):e23792. doi: 10.1002/jbt.23792.
Recently, ezetimibe (EZM) has been suggested to be a potent Nrf2 activator that is important for preventing oxidative stress. Interestingly, we found that its metabolite ezetimibe ketone (EZM-K) also has antioxidant effects. Thus, we investigated the role of EZM-K in preventing renal ischemia‒reperfusion injury (RIRI). Cultured NRK-52E cells were subjected to simulated IR with or without EZM-K. Rats were used to simulate in vivo experiments. EZM-K alleviated HO-induced apoptosis and reactive oxygen species (ROS) and upregulated Nrf2 and HO-1 levels in NRK-52E cells. A HO-1 and a Nrf2 inhibitor reversed the protective effects of EZM-K. In the rat RIRI model, pretreatment with EZM-K activated the Nrf2/HO-1 signaling pathway, suppressed tubular injury and inflammation, and improved renal function. EZM-K significantly prevented renal injury caused by ischemia‒reperfusion via the Nrf2/HO-1 signaling axis both in vivo and in vitro. The other metabolite of EZM, ezetimibe glucuronide (EZM-G) had no protective effects against ROS in RIRI. EZM-G also had no antioxidant effects and could not activate Nrf2/HO-1 signal pathway. Our findings also indicated the therapeutic potential of EZM-K in preventing RIRI.
最近，依折麦布（EZM）被认为是一种有效的 Nrf2 激活剂，对于预防氧化应激非常重要。有趣的是，我们发现其代谢产物依折麦布酮（EZM-K）也具有抗氧化作用。因此，我们研究了 EZM-K 在预防肾缺血再灌注损伤（RIRI）中的作用。培养的 NRK-52E 细胞在有或没有 EZM-K 的情况下进行模拟 IR。使用大鼠模拟体内实验。EZM-K 减轻了 HO 诱导的细胞凋亡和活性氧（ROS），并上调了 NRK-52E 细胞中的 Nrf2 和 HO-1 水平。HO-1 和 Nrf2 抑制剂逆转了 EZM-K 的保护作用。在大鼠 RIRI 模型中，EZM-K 预处理激活了 Nrf2/HO-1 信号通路，抑制了肾小管损伤和炎症，并改善了肾功能。EZM-K 通过 Nrf2/HO-1 信号轴在体内和体外均显著预防了缺血再灌注引起的肾损伤。EZM 的另一种代谢产物依折麦布葡萄糖醛酸（EZM-G）对 RIRI 中的 ROS 没有保护作用。EZM-G 也没有抗氧化作用，不能激活 Nrf2/HO-1 信号通路。我们的研究结果还表明 EZM-K 在预防 RIRI 中的治疗潜力。
