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Abstract: FR-PO1079

miR-150 Inhibitor Ameliorates Three Immune-Involved Kidney Diseases by Reducing Inflammation and Fibrosis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Luan, Junjun, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Qi, Huimeng, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Fu, Jingqi, School of Public Health, China Medical University, Shenyang, Liaoning, China
  • Jiao, Congcong, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Kong, Weiwei, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Chen, Chengjie, School of Public Health, China Medical University, Shenyang, Liaoning, China
  • Cui, Xiangfei, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Pi, Jingbo, School of Public Health, China Medical University, Shenyang, Liaoning, China
  • Wang, Yanqiu, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Li, Detian, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
  • Zhou, Hua, The Affiliated Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
Background

Renal fibrosis from immune-involved kidney diseases remains refractory. We previously reported that miR-150 increased in the repeated renal biopsies from patients with lupus nephritis (LN) and found that miR-150 mimic promoted fibrosis in three human kidney resident cells in vitro. We aimed to clarify whether miR-150 inhibitor can ameliorate renal fibrosis in three kidney disease mouse models and to identify the corresponding mechanisms.

Methods

We first examined miR-150 in renal biopsies from patients with new onset LN or focal segmental glomerulosclerosis (FSGS). Then we observed the time course of renal miR-150 in mouse models including spontaneously developed Fcgr2b−/− LN, adriamycin-induced FSGS, and folic acid-induced tubulointerstitial fibrosis (TIF). Lastly, the efficacy and safety of locked nucleic acid (LNA)-anti-miR-150 (2mg/kg, twice a week) were studied when it was subcutaneously injected to LN mice for 8 weeks, to FSGS mice for 6 weeks, and to TIF mice for 4 weeks. The kidney injury (proteinuria, serological indices, and histology damage on PAS and Masson staining), renal levels of pro-inflammatory cytokines (IFN-γ, IL-6, and TNF-α), profibrotic genes (TGF-β, α-SMA, fibronectin, and collagen1), antifibrotic gene suppressor of cytokine signaling 1 (SOCS1), and the infiltration of lymphocytes and macrophages were investigated in mice with LNA-anti-miR-150 treatment comparisons to the scrambled LNA.

Results

miR-150 was increased in renal biopsies of LN and FSGS patients compared to normal kidneys. miR-150 showed higher expression in the kidneys of mice than in other studied organs. LNA-anti-miR-150 downregulated renal miR-150 levels and ameliorated kidney injury in LN, FSGS, and TIF mice without any organ toxicity. The above observed pro-inflammatory cytokines, profibrotic genes, and the infiltration of lymphocytes and macrophages increased while antifibrotic gene SOCS1 decreased in the kidneys of disease mice. LNA-anti-miR-150 decreased the inflammation, fibrosis, and inflammatory cells while increased SOCS1 compared to the scrambled LNA.

Conclusion

miR-150 inhibitor played important renal protective roles in three immune-involved kidney diseases with final renal fibrosis. This suggests that miR-150 inhibitor might be a promising therapeutic agent for renal fibrosis.

Funding

  • Government Support - Non-U.S.