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

Autor: Xueqing Yu, Junzhe Chen, Xiao R. Huang, Jianguo Wu, Pan Pan, Ying Tang, Wenjing Wu, Hui Y. Lan, Liying Liang, Dingwen Hu, Wenbiao Wang
Rok vydání: 2021
Předmět:
Programmed cell death
Science
General Chemical Engineering
General Physics and Astronomy
Medicine (miscellaneous)
urologic and male genital diseases
Biochemistry
Genetics and Molecular Biology (miscellaneous)
SARS‐CoV‐2
Cell Line
N protein
Mice
Mediator
In vivo
medicine
Animals
Coronavirus Nucleocapsid Proteins
Humans
General Materials Science
Smad3 Protein
Research Articles
TGF‐β
Mice
Knockout
Kidney
p21
integumentary system
SARS-CoV-2
urogenital system
business.industry
fungi
General Engineering
Acute kidney injury
COVID-19
Acute Kidney Injury
Phosphoproteins
G1 cell cycle
medicine.disease
G1 Phase Cell Cycle Checkpoints
female genital diseases and pregnancy complications
Epithelium
Disease Models
Animal
HEK293 Cells
medicine.anatomical_structure
Knockout mouse
Cancer research
business
G1 phase
Research Article
Smad3
Zdroj: Advanced Science
Advanced Science, Vol 9, Iss 3, Pp n/a-n/a (2022)
ISSN: 2198-3844
Popis: 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.
In this article, the authors discover that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) N protein can bind and activate Smad3 to induce kidney cell death and cause acute kidney injury (AKI) via p21‐dependent G1 cell cycle arrest mechanism. Targeting Smad3 with a pharmacological inhibitor SIS3 can inhibit SARS‐CoV‐2 N‐induced AKI.
Databáze: OpenAIRE
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