The Journal of Practical Medicine >

2026 , Vol. 42 >Issue 11: 2037 - 2048

DOI: https://doi.org/10.3969/j.issn.1006-5725.2026.11.019

Treatise：Mechanism and Practice

N6-methyladenosine methylation regulates klotho expression in septic acute kidney injury-underlying mechanism of renal tubular cell senescence

  • Zhu LI ,
  • Shiqi NIE ,
  • Jianglu TAN ,
  • Xiaoyue LI ,
  • Lili TANG ,
  • Zhi KOU
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  • 1.Department of Emergency，the Second Affiliated Hospital of Zunyi Medical University，Zunyi 563000，Guizhou，China
    2.Department of Emergency，the Fifth Affiliated （Zhuhai） Hospital of Zunyi Medical University，Zhuhai 519000，Guangdong，China
    3.Department of Critical Care Medicine，the Fifth Affiliated （Zhuhai） Hospital of Zunyi Medical University，Zhuhai 519000，Guangdong，China

Received date: 2026-01-10

  Online published: 2026-06-15

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Abstract

Objective To elucidate the molecular mechanism whereby N6-methyladenosine （m6A） RNA methylation regulates Klotho expression and drives renal tubular epithelial cell （RTEC） senescence in septic acute kidney injury （SAKI）. Methods An in vitro SAKI cellular model was established using lipopolysaccharide （LPS）-stimulated human proximal tubular epithelial cells （HK-2）. Cell viability， senescence-associated β-galactosidase （SA-β-gal） activity， and global and gene-specific m6A levels were quantified. Functional gain- and loss-of-function experiments were performed via transient transfection of small interfering RNAs （siRNAs） targeting METTL3 or YTHDF2， and plasmid-mediated overexpression of wild-type Klotho or a Klotho mutant lacking functional m6A consensus sites. Results In the SAKI model， RTECs exhibited significantly reduced viability （P < 0.05）， increased SA-β-gal positivity （P < 0.05）， elevated global m6A abundance， and site-specific hypermethylation of Klotho mRNA （P < 0.05）. Concurrently， METTL3 and YTHDF2 protein expression were upregulated （P < 0.05）， whereas Klotho mRNA and protein levels were markedly suppressed （P < 0.05）. METTL3 or YTHDF2 overexpression enhanced m6A deposition on Klotho mRNA （P < 0.05）， accelerated its YTHDF2-dependent decay （P < 0.05）， and consequently diminished Klotho expression （P < 0.05） and exacerbated cellular senescence （P < 0.05）. Conversely， siRNA-mediated knockdown of METTL3 or YTHDF2， or expression of the m6A-site-deficient Klotho mutant， restored Klotho expression and attenuated senescence phenotypes. Conclusion Dysregulated m6A methylation-mediated by METTL3/YTHDF2 axis-promotes RTEC senescence in SAKI through targeted suppression of Klotho. These findings identify the m6A–Klotho regulatory axis as a mechanistically defined and therapeutically relevant pathway in sepsis-induced renal aging.

Key words： N6-methyladenosine; Klotho; cell senescence; septic kidney injury

Cite this article

Zhu LI , Shiqi NIE , Jianglu TAN , Xiaoyue LI , Lili TANG , Zhi KOU . N6-methyladenosine methylation regulates klotho expression in septic acute kidney injury-underlying mechanism of renal tubular cell senescence[J]. The Journal of Practical Medicine, 2026 , 42(11) : 2037 -2048 . DOI: 10.3969/j.issn.1006-5725.2026.11.019

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