Aristolochic acid I aggravates oxidative stress-mediated apoptosis by inhibiting APE1/Nrf2/HO-1 signaling

AbstractNephrotoxicity 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.Keywords: Aristolochic acid IAPE1oxidative stressaristolochic acid nephropathyAPE1/Nrf2/HO-1 Authors’ contributionsQi Zhang wrote the manuscript. Qi Zhang, Lei Tian, Yongkang Hu, Wenjuan Jiang, Xian Wang, Xinlong Guo, Langqun Chen and Siyu Cheng performed the experiments. Jiahui Ying collected the data and did the analysis. Baoping Jiang, Liang Zhang revised the manuscript.Disclosure statementNo potential conflict of interest was reported by the author(s).Date availability statementData can be available upon request from the corresponding author.Additional informationFundingOur studies were supported by Jiangsu Pharmaceutical Association-Aosaikang fund of Hospital Pharmacy Research Project [No. A201802], by Jiangsu Provincial Administration of Chinese Medicine Project [No. YB2020012].