Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-β/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-β/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI.
SARS‐CoV‐2 N Protein Induces Acute Kidney Injury via Smad3‐Dependent G1 Cell Cycle Arrest Mechanism
