Myocardin-related transcription factor A (MRTF-A) contributes to acute kidney injury by regulating macrophage ROS production

Li Liu, Xiaoyan Wu, Huihui Xu, Liming Yu, Xinjian Zhang, Luyang Li, Jianliang Jin, Tao Zhang, Yong Xu

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

A host of pathogenic factors induce acute kidney injury (AKI) leading to insufficiencies of renal function. In the present study we evaluated the role of myocardin-related transcription factor A (MRTF-A) in the pathogenesis of AKI. We report that systemic deletion of MRTF-A or inhibition of MRTF-A activity with CCG-1423 significantly attenuated AKI in mice induced by either ischemia-reperfusion or LPS injection. Of note, MRTF-A deficiency or suppression resulted in diminished renal ROS production in AKI models with down-regulation of NAPDH oxdiase 1 (NOX1) and NOX4 expression. In cultured macrophages, MRTF-A promoted NOX1 transcription in response to either hypoxia-reoxygenation or LPS treatment. Interestingly, macrophage-specific MRTF-A deletion ameliorated AKI in mice. Mechanistic analyses revealed that MRTF-A played a role in regulating histone H4K16 acetylation surrounding the NOX gene promoters by interacting with the acetyltransferase MYST1. MYST1 depletion repressed NOX transcription in macrophages. Finally, administration of a MYST1 inhibitor MG149 alleviated AKI in mice. Therefore, we data illustrate a novel epigenetic pathway that controls ROS production in macrophages contributing to AKI. Targeting the MRTF-A-MYST1-NOX axis may yield novel therapeutic strategies to combat AKI.

Original languageEnglish (US)
Pages (from-to)3109-3121
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number10
DOIs
StatePublished - Oct 2018
Externally publishedYes

Keywords

  • Acute kidney injury
  • Epigenetics
  • Macrophage
  • ROS
  • Transcriptional regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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