Aristolochic acid I abnormally activates the wnt7b/β-catenin signaling pathway and affects the repair of renal tubules

Abstract

Aristolochic acid I (AAI), which is one of the main forms of aristolochic acid, can cause aristolochic acid nephropathy. Abnormal activation or inhibition of the Wnt7b/β-catenin signaling pathway may lead to the occurrence and development of kidney disease. This study aimed to investigate the effect of the Wnt7b/β-catenin signaling pathway on the damage and repair processes of renal tubular epithelial cells (RTECs) using mouse and zebrafish models of acute aristolochic acid intoxication. Our data revealed that after mice were exposed to 5 mg/kg/day AAI for 4 days and 6 days the expression of Wnt7b on the villi of RTECs increased, the expression of β-catenin on the cytoplasm decreased, and the expression of β-catenin in the nucleus increased. The protein expression levels of PCNA and Kim-1 increased. After zebrafish at 3 days post fertilization were exposed to 2, 4, and 8 μg/mL AAI for 24 h, the results indicated that treatment with AAI resulted in a decrease in the number of RTECs and the occurrence of apoptosis. Importantly, after knockout of the Wnt7ba gene, damage to RTECs in zebrafish larvae was aggravated, the mRNA expression level of PCNA decreased, and that of Kim-1 increased. In addition, we found that AAI exhibits developmental toxicity in fertilized zebrafish eggs. As a result, AAI leads to abnormal activation of the Wnt7b/β-catenin signaling pathway, which affects the repair of renal tubular injury by activating the downstream protein PCNA. The Wnt7ba gene may serve as a potential therapeutic target to promote repair after renal tubular injury.