NSUN2 Exacerbates Renal Fibrosis by Inducing Epithelial-Mesenchymal Transition Through Mediating m5C Modification of

Chongxiang Xiong1, Ruiyi Gan1, Shangrui Li1

  • 1Department of Nephrology, The First Affiliated Hospital of Dongguan Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.

Insights

The RNA modification NSUN2 (5-methylcytosine methyltransferase) promotes kidney fibrosis by stabilizing BRD4 mRNA. Upregulated BRD4 then enhances PDPK1 expression, driving epithelial-mesenchymal transition and fibrosis.

Area of Science:

  • Molecular Biology
  • Renal Pathophysiology
  • Epigenetics

Background:

  • 5-methylcytosine (m5C) is a key RNA modification involved in diverse biological functions.
  • Renal fibrosis is a significant contributor to kidney disease progression.
  • The role of m5C methyltransferase NSUN2 in renal fibrosis remains incompletely understood.

Purpose of the Study:

  • To investigate the molecular mechanisms by which NSUN2 regulates renal fibrotic progression.
  • To elucidate the role of NSUN2-mediated m5C modification in epithelial-mesenchymal transition (EMT).

Main Methods:

  • Sirius red staining for collagen deposition.
  • MeRIP and RIP assays for m5C methylation and RNA-protein interactions.
  • Dual-luciferase assay, ChIP, RT-qPCR, western blotting, and immunohistochemistry for molecular mechanism validation.
  • Unilateral Ureteral Obstruction (UUO) rat model for in vivo fibrosis assessment.

Main Results:

  • NSUN2 expression was elevated in fibrotic renal tissues and cells.
  • NSUN2 knockdown ameliorated renal fibrosis in UUO rats and inhibited TGF-β1-induced EMT in HK-2 cells.
  • NSUN2 stabilized BRD4 mRNA via m5C modification and ALYREF interaction, increasing BRD4 expression.
  • BRD4 enhanced H3K27ac enrichment at the PDPK1 promoter, boosting PDPK1 expression and activating the AKT1/GSK-3β pathway, thereby inducing EMT.

Conclusions:

  • NSUN2 promotes renal fibrosis by stabilizing BRD4 mRNA in an m5C-ALYREF-dependent manner.
  • Upregulated BRD4 drives renal fibrosis through H3K27ac-mediated PDPK1 induction and subsequent activation of the AKT1/GSK-3β signaling pathway, ultimately promoting EMT.

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