Pneumonia activates renal antioxidant defense function to reduce the damage of aristolochic acid I through Keap1/Nrf2/NQO1 signaling pathway

Aristolochic acids (AAs) are a group of compounds widely found in Aristolochiaceae, and the main toxic component of AAs is aristolochic acid I (AAI). AAI causes severe direct nephrotoxicity and carcinogenicity. Plants containing AAI are widely used around the world; for example, Asari Radix et Rhizoma (ARR) contains trace amounts of aristolochic acid and is still included in the Chinese Pharmacopoeia. Based on the theory of therapy for syndrome differentiation in traditional Chinese medicine, we established a 7-day mouse model of pneumonia and observed that kidney damage in the pneumonia group was significantly lower than that in the healthy group after the same treatment. Subsequently, the carcinogenic metabolite aristolochic acid-DNA adduct standards were synthesized, and assays were established. No adduct formation was detected in our limit of quantification (500 pg/ml) in the ARR group, while the adduct formation in the Caulis Aristolochiae Manshuriensis (CAM) group, whose content of AAI is 900 times that of the ARR, was significantly lower than that in the healthy group in the pneumonia state. Here, we demonstrate that the safety risk of ARR is not high at normal doses. Western blot analysis revealed that the level of the AAI metabolic enzyme NQO1 in the pneumonia group was significantly lower than that in the healthy group. Combined with the transcriptomic results, we speculate that kidney injury and adduct production in the pneumonia group were lower than those in the healthy group because of the ROS-Keap1-Nrf2-NQO1 pathway.