SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism

Advanced Science

卷:9

Ying Tang¹  Wenjing Wu²  Liying Liang²  Wenbiao Wang²  Xiao R. Huang²  Hui Y. Lan²  Junzhe Chen²  Jianguo Wu³  Pan Pan³  Xueqing Yu⁴  Dingwen Hu⁵ 

[1] Department of Nephrology The Third Affiliated Hospital Southern Medical University Guangzhou 510080 China;

[2] Departments of Medicine and Therapeutics Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine The Chinese University of Hong Kong Hong Kong 999077 China;

[3] Guangdong Provincial Key Laboratory of Virology Institute of Medical Microbiology Jinan University Guangzhou 510632 China;

[4] Guangdong‐Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease Guangdong Academy of Medical Science Guangdong Provincial People's Hospital Guangzhou 510080 China;

[5] State Key Laboratory of Virology College of Life Sciences Wuhan University Wuhan 430072 China;

关键词: acute kidney injury;    G1 cell cycle;    N protein;    p21;    SARS‐CoV‐2;    Smad3;   

DOI  :  10.1002/advs.202103248

来源: DOAJ

【 摘 要 】

Abstract COVID‐19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID‐19 and acute kidney injury (AKI) is common in critically ill COVID‐19 patients. However, mechanisms through which COVID‐19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney‐specifically overexpressing SARS‐CoV‐2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS‐CoV‐2 N‐induced AKI is Smad3‐dependent as SARS‐CoV‐2 N protein can interact with Smad3 and enhance TGF‐β/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS‐CoV‐2 N protein‐induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS‐CoV‐2 N‐induced AKI. In conclusion, the authors identify that SARS‐CoV‐2 N protein is a key mediator for AKI and induces AKI via the Smad3‐dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID‐19‐asscoaited AKI.

【 授权许可】

Unknown