(P01-016-23) Lycopene Protects Against Atrazine-Induced Kidney STING-Dependent Panoptosis Through Stabilizing mtDNA via Interaction With sam50/PHB1

Objectives: Atrazine (ATR), one of the most widely used broadleaf weed herbicides globally, can accumulate continuously in soil and water environments, causing toxic effects on animal and human kidneys. Lycopene (LYC) is a carotenoid with numerous biological activities and antioxidant properties that, due to its potent anti-inflammatory effects, plays an important role in kidney protection. The purpose of this study was to investigate the role of LYC in ATR-induced mtDNA leakage contributes to kidney inflammation and PANoptosis.

Methods: SPF mice were randomly divided into seven groups: Con, Vcon, 5 mg/kg LYC, 50 mg/kg and 200 mg/kg ATR, or 50 mg/kg or 200 mg/kg ATR+5 mg/kg LYC were treated with gavage for 21 days. The histopathology and ultrastructure of kidney were observed. qRT-PCR, western blot, and immunofluorescence staining were conducted to detect gene and protein levels of mtDNA leakage markers, inflammatory factors, PANoptosis and cGAS-STING signaling pathway related factors. Molecular docking and was used to validate the interaction.

Results: Histopathological analysis and ultrastructural observation found that LYC alleviated ATR-induced renal tubule injury and mitochondrial crest blurring. The results of qRT-PCR, molecular docking, and western blot exhibited that LYC not only alleviated ATR-induced cGAS-STING pathway activation and the expression of its downstream genes but also reduced the expression of inflammation-related factors and PANoptotic markers. In addition, LYC also restored the high expression of mitochondrial leakage indicators, the reduction of mitochondrial stability, and the elevated mitochondrial inner and outer membrane permeability.

Conclusions: LYC alleviates ATR-induced mitochondrial membrane damage and mtDNA leakage, thereby inhibiting the activation of cGAS-STING pathway and alleviating renal inflammation and PANoptosis. This study explores the mechanism of LYC inhibiting ATR-induced kidney injury, which is of great significance for the clinical use of LYC in the treatment of kidney diseases and the selection of new therapeutic targets.

Funding Sources: Joint Guidance Project of Natural Science Foundation of Heilongjiang Province of China (No. LH2021C045).
*Corresponding author: Dr. Xue-Nan Li. E-mail address: lixuenan@neau.edu.cn