The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression

Juan Cai, Zhiwen Liu, Xian Huang, Shaoqun Shu, Xiaoru Hu, Meiling Zheng, Chengyuan Tang, Yu Liu, Guochun Chen, Lin Sun, Hong Liu, Fuyou Liu, Jinke Cheng, Zheng Dong

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Fibrosis is a common pathologic pathway of progressive kidney disease involving complex signaling networks. The deacetylase sirtuin 6 (sirt6) was recently implicated in kidney injury. However, it remains elusive whether and how sirt6 contributes to the regulation of kidney fibrosis. Here, we demonstrate that sirt6 protects against kidney interstitial fibrosis through epigenetic regulation of β-catenin signaling. Sirt6 is markedly upregulated during fibrogenesis following obstructed nephropathy and kidney ischemia-reperfusion injury. Pharmacological inhibition of sirt6 deacetylase activity aggravates kidney fibrosis in obstructed nephropathy. Consistently, knockdown of sirt6 in mouse kidney proximal tubular epithelial cells aggravates transforming growth factor-β-induced fibrosis in vitro. Mechanistically, sirt6 deficiency results in augmented expression of the downstream target proteins of β-catenin signaling. We further show that sirt6 interacts with β-catenin during transforming growth factor-β treatment and binds to the promoters of β-catenin target genes, resulting in the deacetylation of histone H3K56 to prevent the transcription of fibrosis-related genes. Thus, our data reveal the anti-fibrotic function of sirt6 by epigenetically attenuating β-catenin target gene expression.

Original languageEnglish (US)
Pages (from-to)106-118
Number of pages13
JournalKidney International
Volume97
Issue number1
DOIs
StatePublished - Jan 2020
Externally publishedYes

Keywords

  • IR
  • TGF-β
  • UUO
  • renal fibrosis
  • sirtuin 6
  • β-catenin

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Cai, J., Liu, Z., Huang, X., Shu, S., Hu, X., Zheng, M., Tang, C., Liu, Y., Chen, G., Sun, L., Liu, H., Liu, F., Cheng, J., & Dong, Z. (2020). The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression. Kidney International, 97(1), 106-118. https://doi.org/10.1016/j.kint.2019.08.028