Ezetimibe ketone protects against renal ischemia–reperfusion injury and attenuates oxidative stress via activation of the Nrf2/HO‐1 signaling pathway

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 H 2 O 2 ‐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.