2. Academic Validation
  3. Hydrogen sulfide attenuates renal fibrosis by inducing TET-dependent DNA demethylation on Klotho promoter

Hydrogen sulfide attenuates renal fibrosis by inducing TET-dependent DNA demethylation on Klotho promoter

  • FASEB J. 2020 Sep;34(9):11474-11487. doi: 10.1096/fj.201902957RR.
Yulu Gu 1 2,  Jing Chen 1 3,  Han Zhang 1 3,  Ziyan Shen 1 3,  Hong Liu 1 3,  Shiqi Lv 1 2,  Xixi Yu 1 2,  Di Zhang 1 2,  Xiaoqiang Ding 1 2 3 4,  Xiaoyan Zhang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
  • 3 Shanghai Medical Center of Kidney Disease, Shanghai, China.
  • 4 Shanghai Institute of Kidney and Dialysis, Shanghai, China.
PMID: 32729950 DOI: 10.1096/fj.201902957RR
Abstract

Hypoxia is a key pathogenetic characteristic of chronic kidney disease (CKD). Klotho has renoprotective effect and its expression is commonly suppressed in CKD patients. We showed that chronic hypoxia in unilateral ureteral obstruction model mice is associated with renal Klotho promoter methylation and expression silencing. Administration of low-dose of sodium hydrosulfide (NaHS) effectively ameliorated renal tubulointerstitial fibrosis in the mouse model by demethylating Klotho promoter and restoring its expression. Mechanistically, hypoxia microenvironment in CKD reduced cellular oxygen availability and Fe2+ concentration, and led to impaired activity of ten-eleven translocation (TET), which is critical in maintaining Klotho promoter demethylation status. NaHS treatment greatly improved hypoxia condition, restored TET activity, reversed DNA methylation, and thus, increased Klotho expression. Our results strongly suggested that correcting hypoxia condition to restore TET activity could be a promising therapeutic strategy against CKD.

Keywords

CKD; Fe2+; ROS; hypoxia.

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