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Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation
Demin Cheng, … , Yi Liu, Chunhui Ni
Demin Cheng, … , Yi Liu, Chunhui Ni
Published September 27, 2022
Citation Information: JCI Insight. 2022;7(22):e162831. https://doi.org/10.1172/jci.insight.162831.
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Research Article Pulmonology

Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation

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Abstract

Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that TGF-β1–mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts. Thus, intravenous administration of UHRF1 siRNA–loaded liposomes significantly protected mice against experimental pulmonary fibrosis. Accordingly, our data suggest that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.

Authors

Demin Cheng, Yue Wang, Ziwei Li, Haojie Xiong, Wenqing Sun, Sichuan Xi, Siyun Zhou, Yi Liu, Chunhui Ni

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Figure 2

UHRF1 regulates TGF-β1–induced lung fibroblast proliferation.

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UHRF1 regulates TGF-β1–induced lung fibroblast proliferation.
(A) qRT-PC...
(A) qRT-PCR analysis of UHRF1 expression in MRC-5 cells and PLFs transfected with UHRF1 siRNA or its negative control (NC) siRNA, Data are shown as the mean ± SEM (n = 3 in each group). (B and C) Western blot and corresponding densitometry analysis of fibronectin, collagen I, and α-SMA in MRC-5 cells and PLFs transfected with UHRF1 siRNA and its negative control siRNA and then treated with 5 ng/mL TGF-β1 for 48 hours. Data are shown as the mean ± SEM (n = 3 in each group). (D) The expression of α-SMA was detected by immunofluorescence staining in MRC-5 cells transfected with UHRF1 siRNA and its negative control siRNA and then treated with 5 ng/mL TGF-β1 for 48 hours. (E) Mean fluorescence intensity of α-SMA in MRC-5 cells from the different groups. Data are shown as the mean ± SEM (n = 3 in each group). (F and G) Proliferation of MRC-5 cells transfected with UHRF1 siRNA and its negative control siRNA, as assessed by EdU assays. Data are shown as the mean ± SEM (n = 3 in each group). (H) Effect of UHRF1 siRNA and its negative control siRNA on the contractility of TGF-β1–induced fibroblasts. Scale bar: 50 μm (D); 100 μm (F). (A, C, E, and G) P values were from a 1-way ANOVA post hoc test with Tukey’s correction.

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