Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest

作者：Wu, Wenjing; Wang, Wenbiao; Liang, Liying; Chen, Junzhe; Wei, Biao; Huang, Xiao-Ru; Wang, Xiaoqin^*; Yu, Xueqing^*; Lan, Hui-Yao^*

来源：Molecular Therapy, 2023, 31(2): 344-361.

DOI：10.1016/j.ymthe.2022.12.002

• TRADITIONAL CHINESE MEDICINE
• NUCLEOCAPSID PROTEIN
• EARLY-STAGE
• COVID-19
• INFECTION
• STRESS

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains inef-fective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treat-ment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibit-ing Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin maybe an effective TCM compound capable of inhib-iting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.

• 单位
  南方医科大学; 广东省人民医院