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Abstract: PO2480

Targeting Histone Demethylase LDS1 Inhibits Renal Epithelial-Mesenchymal Transition and Attenuates Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Zhang, Xiaoqin, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Agborbesong, Ewud, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background

Lysine-specific histone demethylase 1 (LSD1) as the first identified protein demethylase plays a special role in the regulation of gene expression by removing methyl groups from mono- and di-methylated lysine 4 and 9 on histone H3 and functions as an oncogenic factor in cancers. However, its role in renal fibrosis is unknown.

Methods

To evaluate the role and mechanisms of LSD1 in the development of renal epithelial–mesenchymal transition (EMT) and renal fibrosis, we inhibited LSD1 with its inhibitor, ORY1001, in mouse unilateral ureter obstruction (UUO) model and rat kidney fibroblasts (NRK-49F) and rat kidney proximal tubular (NRK-52E) cells stimulated by TGF-β1.

Results

We found that the expression of LSD1 was increased and the methylation of its histone targets were decreased in mouse kidneys with unilateral ureteral obstruction and NRK-52E cells undergoing EMT. Inhibition of LSD1 with ORY1001 decreased the deposition of extracellular matrix proteins and the expression of fibrotic markers, including α-smooth muscle actin (α-SMA) and fibronectin, which was associated with preserving E-cadherin expression and inhibiting N-cadherin upregulation in the obstructed kidney. Injury to the kidney enhanced the phosphorylation and activation of Smad2/3, AKT and Stat3, and that could be prevented by ORY1001 administration. Targeting LSD1 with ORY1001 and siRNAs inhibited TGFβ1 induced the activation of renal fibroblasts, NRK-49F, and EMT of NRK-52E cells. The expression of Snail family transcriptional repressor 1 (Snail-1) was upregulated in UUO kidneys and cultured NRK-52E cells treated with TGFβ1. Snail-1 repressed the expression of E-cadherin via the interaction of its N-terminal SNAG domain with LSD1. LSD1 inhibition with ORY1001 or siRNA silencing prevented the upregulation of Snail-1 and disrupted Snail/LSD1 interaction, resulting in the expression of E-cadherin. ORY1001 was also effective in suppressing TGF-β1-induced renal epithelial cells arrest at the G2/M phase.

Conclusion

This study indicates that LSD1 participates in the expression of profibrotic genes and contributes to renal EMT and fibrosis through activation of diverse signaling pathways, and places an emphasis that LSD1 has potential as a therapeutic target for the treatment of renal fibrosis.

Funding

  • Other NIH Support