NAT10 Drives Kidney Cell Aging in Cisplatin Injury via DDX17 Pathway
Scientists identify NAT10 as a key driver of tubular cell senescence in cisplatin-induced AKI, revealing a novel NAT10/DDX17 therapeutic target.
Summary
Researchers from Huazhong University of Science and Technology found that NAT10, an acetyltransferase enzyme, is significantly upregulated in kidney tubular cells during cisplatin-induced acute kidney injury (AKI). Using mouse models and human HK-2 tubular cells, they showed that NAT10 promotes cellular senescence — permanent cell cycle arrest linked to inflammation and fibrosis. Knocking down NAT10 genetically or blocking it with the inhibitor Remodelin reduced kidney damage, lowered senescence markers (p53, p21, γ-H2A.X), and suppressed inflammatory SASP factors (IL-1β, IL-6, TNF-α). The mechanism involves NAT10 physically interacting with and stabilizing DDX17, an RNA helicase that independently drives senescence. Silencing DDX17 alone blunted cisplatin-induced senescence, and DDX17 restoration reversed NAT10-knockdown protection, confirming the NAT10/DDX17 axis as the operative pathway.
Detailed Summary
Acute kidney injury (AKI) affects millions annually and carries high mortality, with cisplatin chemotherapy responsible for AKI in roughly one-third of treated cancer patients. A poorly understood feature of cisplatin-induced AKI is premature cellular senescence in renal tubular epithelial cells — a state of permanent growth arrest that unleashes pro-inflammatory and pro-fibrotic signals capable of driving progression to chronic kidney disease. Identifying molecular drivers of this senescence program is therefore of significant clinical importance.
This study implicates N-acetyltransferase 10 (NAT10) — an enzyme with both protein and RNA acetyltransferase activities — as a central promoter of tubular senescence during cisplatin-induced AKI. NAT10 mRNA and protein levels rose progressively in mouse kidney cortex from day 1 to day 3 after cisplatin injection, with immunofluorescence confirming upregulation specifically in proximal tubular epithelial cells. Parallel dose- and time-dependent increases were observed in human HK-2 tubular cells treated with cisplatin.
Genetic knockdown of NAT10 via lentiviral delivery into the renal cortex significantly improved kidney function (lower serum creatinine and BUN), reduced tubular injury scores on H&E histology, decreased expression of injury markers NGAL and KIM-1, and blunted reactive oxygen species generation. Critically, NAT10 knockdown markedly suppressed senescence, reducing SA-β-galactosidase activity, downregulating p53, p21, and γ-H2A.X, and lowering SASP cytokines IL-1β, IL-6, and TNF-α. Pharmacological inhibition with Remodelin (20 mg/kg IP) reproduced these benefits, and safety testing showed no hepatotoxicity or weight loss after 30 consecutive days of Remodelin administration.
RNA-sequencing of NAT10-silenced HK-2 cells identified DDX17, a DEAD-box RNA helicase, as a key downstream target. Co-immunoprecipitation confirmed direct physical interaction between NAT10 and DDX17, and NAT10 knockdown or Remodelin treatment reduced DDX17 protein — but not mRNA — levels, indicating post-translational regulation. Cycloheximide chase experiments showed accelerated DDX17 protein degradation when NAT10 was absent, suggesting NAT10 stabilizes DDX17. Silencing DDX17 alone phenocopied NAT10 knockdown in suppressing cisplatin-induced senescence, and restoring DDX17 in NAT10-depleted cells rescued the senescent phenotype, confirming DDX17 as the functional effector of NAT10's pro-senescence activity.
The study positions the NAT10/DDX17 signaling axis as a novel, druggable pathway in cisplatin-induced AKI. Remodelin, already known for extending healthspan in accelerated-aging mouse models, may merit investigation as a nephroprotective adjunct during cisplatin chemotherapy. Key caveats include reliance on a single AKI model (cisplatin), use of a commercially available human cell line, and absence of AKI-to-CKD transition data, which will be important for future work.
Key Findings
- NAT10 expression rises progressively in mouse renal tubular cells and human HK-2 cells following cisplatin exposure.
- NAT10 knockdown or Remodelin treatment reduces kidney injury markers, oxidative stress, and tubular damage scores in vivo.
- NAT10 suppression markedly decreases cellular senescence markers p53, p21, γ-H2A.X and SASP cytokines IL-1β, IL-6, TNF-α.
- NAT10 physically interacts with DDX17 and stabilizes its protein, driving senescence; DDX17 silencing alone blocks cisplatin-induced senescence.
- Remodelin showed no hepatotoxicity or overt toxicity after 30 days of continuous administration in mice.
Methodology
The study used male C57BL/6J mice injected with 25 mg/kg cisplatin IP alongside lentiviral NAT10 knockdown delivered by renal cortex injection or pharmacological inhibition with Remodelin (20 mg/kg IP). In vitro work used cisplatin-treated HK-2 human proximal tubular cells with lentiviral knockdown, siRNA, overexpression plasmids, and co-immunoprecipitation/LC-MS proteomics to define the NAT10-DDX17 interaction.
Study Limitations
The study relies exclusively on a cisplatin AKI model; generalizability to ischemia-reperfusion or sepsis-induced AKI is unconfirmed. All in vivo work used a single male mouse strain, limiting translational scope. Long-term outcomes including AKI-to-CKD progression were not assessed, and the precise mechanism by which NAT10 post-translationally stabilizes DDX17 protein remains to be fully elucidated.
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