1. Academic Validation
  2. Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis-Associated Acute Kidney Injury

Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis-Associated Acute Kidney Injury

  • Adv Sci (Weinh). 2024 May 20:e2307216. doi: 10.1002/advs.202307216.
Jiao Qiao 1 2 3 Yuan Tan 1 2 3 Hongchao Liu 2 3 Boxin Yang 2 3 Qian Zhang 2 3 Qi Liu 1 2 3 Wenyuan Sun 2 3 Zhongxin Li 2 3 Qingchen Wang 2 3 Weimin Feng 1 2 3 Shuo Yang 2 3 Liyan Cui 1 2 3
Affiliations

Affiliations

  • 1 Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China.
  • 2 Department of Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, China.
  • 3 Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, Beijing, 100191, China.
Abstract

Histone lactylation is a metabolic stress-related histone modification. However, the role of histone lactylation in the development of sepsis-associated acute kidney injury (SA-AKI) remains unclear. Here, histone H3K18 lactylation (H3K18la) is elevated in SA-AKI, which is reported in this study. Furthermore, this lactate-dependent histone modification is enriched at the promoter of Ras homolog gene family member A (RhoA) and positively correlated with the transcription. Correction of abnormal lactate levels resulted in a reversal of abnormal histone lactylation at the promoter of RhoA. Examination of related mechanism revealed that histone lactylation promoted the RhoA/Rho-associated protein kinase (ROCK) /Ezrin signaling, the activation of nuclear factor-κB (NF-κB), inflammation, cell Apoptosis, and aggravated renal dysfunction. In addition, Ezrin can undergo lactylation modification. Multiple lactylation sites are identified in Ezrin and confirmed that lactylation mainly occurred at the K263 site. The role of histone lactylation is revealed in SA-AKI and reportes a novel post-translational modification in Ezrin. Its potential role in regulating inflammatory metabolic adaptation of renal proximal tubule epithelial cells is also elucidated. The results provide novel insights into the epigenetic regulation of the onset of SA-AKI.

Keywords

RhoA; ezrin; glycolysis; lactylation; sepsis‐associated acute kidney injury.

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