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

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.

Automated summary

Increasing evidence suggests that SARS-CoV-2 can cause acute kidney injury (AKI) in COVID-19 patients, but the mechanisms are unclear and treatments are ineffective. This study found that overexpression of the SARS-CoV-2 N gene in the kidneys of diabetic mice led to AKI, and treatment with quercetin, a traditional Chinese medicine compound, inhibited AKI by blocking the interaction between the SARS-CoV-2 N protein and Smad3. This study highlights the pathogenic role of the SARS-CoV-2 N protein in AKI and identifies quercetin as a potential treatment for COVID-19-induced AKI.