Abstract
Nephrotoxicity induced by aristolochic acid I (AAI) is related to redox stress and apoptosis. Apurinic/apyrimidine endonuclease 1 (APE1) has antioxidant and anti-apoptotic effects. This study investigated the potential role of APE1 in AAI-induced nephrotoxicity. Renal injury was successfully induced in C57BL/6J mice by intraperitoneal injection of AAI every other day for 28 days. Expressions of APE1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) in renal tissues of the model mice was inhibited, accompanied by oxidative damage and apoptosis. Similar results were obtained in vitro in human proximal tubular (HK-2) cells damaged by AAI. In the presence of a low concentration of the APE1 inhibitor E3330, expression of Nrf2 and HO-1 proteins in HK-2 cells was decreased and AAI-induced apoptosis was aggravated. Overexpression of APE1 in HK-2 cells promoted the expression of Nrf2 and HO-1, and alleviated apoptosis and renal injury induced by AAI. The collective findings demonstrate that AAI can inhibit the induction of oxidative stress and apoptosis by the APE1/Nrf2/HO-1 axis, leading to AAI renal injury. Targeting APE1 may be an effective therapeutic strategy to treat AA nephrotoxicity.