miR-150-Based RNA Interference Attenuates Tubulointerstitial Fibrosis through the SOCS1/JAK/STAT Pathway In Vivo and In Vitro

Molecular Therapy: Nucleic Acids

Xiangfei Cui¹  Yanqiu Wang¹  Congcong Jiao¹  Junjun Luan¹  Dongdong Wang¹  Hua Zhou¹  Yixiao Zhang²  Jeffrey B. Kopp³  Jingqi Fu⁴  Dan Liu⁴  Chengjie Chen⁴  Jingbo Pi⁴  Peter S.T. Yuen⁵ 

[1] Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China;Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China;Kidney Disease Section, NIDDK, NIH, Bethesda, MD, USA;Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, China;Renal Diagnostics and Therapeutics Unit, NIDDK, NIH, Bethesda, MD, USA;

关键词: RNAi;    renal fibrosis;    macrophages;    SOCS1;    folic acid;    HK-2 cells;   

DOI  :  

来源: DOAJ

【 摘 要 】

We investigated whether microRNA-150 (miR-150)-based RNA interference (RNAi) ameliorates tubular injury and tubulointerstitial fibrosis. Mice injected with folic acid developed tubulointerstitial fibrosis at day 30. miR-150 levels were increased at day 7 and peaked at day 30. At day 30, protein levels of α-smooth muscle actin, fibronectin (FN), and collagen 1 (COL-1) were increased, while suppressor of cytokine signal 1 (SOCS1) was decreased. Kidneys manifested increased macrophage numbers and increased expression of potential mediators: interferon-γ, interleukin-6, and tumor necrosis factor-α. Locked nucleic acid-anti-miR-150, started prior to or after tubular injury and administered twice weekly for 4 weeks, reversed renal inflammation and fibrosis. In HK-2 cells, co-culture with macrophages increased miR-150 expression and decreased SOCS1. Janus kinase (JAK) and signal transducer and activators of transcription (STAT) pathway-related proteins p-JAK1, p-JAK2, p-STAT1, p-STAT3, and pro-fibrotic genes encoding α-smooth muscle actin, FN, and COL-1 were all upregulated. The miR-150 antagonist reversed these transcriptional changes. Lastly, in renal biopsies from patients with chronic interstitial fibrosis, renal miR-150, and pro-fibrotic gene expression and macrophage numbers were increased, while SOCS1 expression was decreased. In conclusion, miR-150-based RNAi is as a potential novel therapeutic agent for tubulointerstitial fibrosis, suppressing the SOCS1/JAK/STAT pathway and reducing macrophage influx.

【 授权许可】

Unknown