Hypermethylation suppresses microRNA-219a-2 to activate the ALDH1L2/GSH/PAI-1 pathway for fibronectin degradation in renal fibrosis

  • Res Sq. 2023 Jun 5:rs.3.rs-2986934. doi: 10.21203/rs.3.rs-2986934/v1.
Xiao Xiao  1 ,  Emily Huo  2 ,  Chunyuan Guo  3 ,  Xiangjun Zhou  4 ,  Xiaoru Hu  5 ,  Charles Dong  6 ,  Huidong Shi  6 ,  Zheng Dong  6 ,  Qingqing Wei  7
Affiliations
  • 1. Zhongnan Hospital of Wuhan University.
  • 2. Augusta Preparatory Day School.
  • 3. Shanghai Skin Disease Hospital, Tongji University School of Medicine.
  • 4. Renmin Hospital of Wuhan University.
  • 5. The Second Xiangya Hospital at Central South University.
  • 6. Augusta University.
  • 7. Augusta University/Medical College of Georgia.
PMID: 37333081 DOI: 10.21203/rs.3.rs-2986934/v1
Abstract

Epigenetic regulations, such as DNA methylation and MicroRNAs, play an important role in renal fibrosis. Here, we report the regulation of microRNA-219a-2 (mir-219a-2) by DNA methylation in fibrotic kidneys, unveiling the crosstalk between these epigenetic mechanisms. Through genome-wide DNA methylation analysis and pyro-sequencing, we detected the hypermethylation of mir-219a-2 in renal fibrosis induced by unilateral ureter obstruction (UUO) or renal ischemia/reperfusion, which was accompanied by a significant decrease in mir-219a-5p expression. Functionally, overexpression of mir-219a-2 enhanced fibronectin induction during hypoxia or TGF-β1 treatment of cultured renal cells. In mice, inhibition of mir-219a-5p suppressed fibronectin accumulation in UUO kidneys. ALDH1L2 was identified to be the direct target gene of mir-219a-5p in renal fibrosis. Mir-219a-5p suppressed ALDH1L2 expression in cultured renal cells, while inhibition of mir-219a-5p prevented the decrease of ALDH1L2 in UUO kidneys. Knockdown of ALDH1L2 enhanced PAI-1 induction during TGF-β1 treatment of renal cells, which was associated with fibronectin expression. In conclusion, the hypermethylation of mir-219a-2 in response to fibrotic stress attenuates mir-219a-5p expression and induces the up-regulation of its target gene ALDH1L2, which may reduce fibronectin deposition by suppressing PAI-1.

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