NAT10 Promotes Tubular Epithelial Cell Senescence in Cisplatin-Induced Acute Kidney Injury by Regulating DDX17.

NAT10 is significantly upregulated in tubular epithelial cells of cisplatin-induced acute kidney injury.

• NAT10 upregulation was observed in tubular epithelial cells in the cisplatin-induced AKI model.
• The finding was established in both in vivo kidney tissue and in vitro tubular epithelial cell models.
• NAT10 is an N-acetyltransferase whose role in AKI pathogenesis was previously incompletely understood.

Lentivirus-mediated knockdown of NAT10 or treatment with the NAT10 inhibitor Remodelin ameliorated cisplatin-induced renal dysfunction and tubular injury.

• Both genetic knockdown (lentivirus-mediated) and pharmacological inhibition (Remodelin) approaches were used to reduce NAT10 activity.
• Both interventions resulted in amelioration of cisplatin-induced renal dysfunction.
• Tubular injury was reduced upon NAT10 inhibition or knockdown.

NAT10 inhibition markedly attenuated cellular senescence in cisplatin-induced AKI.

• Senescence attenuation was evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity.
• Senescence markers p53, p21, and γ-H2A.X were downregulated upon NAT10 inhibition.
• Levels of senescence-associated secretory phenotype (SASP) factors IL-1β, IL-6, and TNF-α were decreased.
• Effects were observed in both in vivo and in vitro cisplatin-injury models.

NAT10 physically interacts with DDX17 and regulates its expression.

• Co-immunoprecipitation assay demonstrated that NAT10 interacted with DDX17.
• Knockdown or inhibition of NAT10 reduced the protein expression of DDX17 in cisplatin-injured kidneys.
• This interaction represents a novel mechanistic link between NAT10 and DDX17 in the context of AKI.

Silencing DDX17 inhibited cisplatin-induced senescence in HK-2 cells.

• DDX17 knockdown experiments were conducted in HK-2 human proximal tubular epithelial cells.
• DDX17 silencing reduced cisplatin-induced cellular senescence.
• This finding establishes DDX17 as a downstream mediator of senescence signaling in tubular epithelial cells.

The effects of NAT10 on cisplatin-induced tubular injury and senescence were dependent on DDX17.

• Rescue or epistasis experiments demonstrated that NAT10's pro-senescence effects required DDX17.
• The NAT10/DDX17 axis was identified as a novel signaling pathway regulating tubular cell senescence.
• These findings suggest that both components of the axis are necessary for the full pathological effect of cisplatin-induced senescence.