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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 5

Beclin 1 is a functional downstream gene of UHRF1 and negatively regulates cell proliferation.

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Beclin 1 is a functional downstream gene of UHRF1 and negatively regulat...
(A) qRT-PCR analysis of beclin 1 expression in MRC-5 cells and PLFs after treatment with TGF-β1. Data are shown as the mean ± SEM (n = 3 in each group). (B–D) Western blot and corresponding densitometry analysis of fibronectin, collagen I, α-SMA, and beclin 1 in beclin 1 siRNA–treated MRC-5 cells and PLFs or those treated with its negative control (NC) siRNA. Data are shown as the mean ± SEM (n = 3 in each group). (E) Immunohistochemical staining of α-SMA in MRC-5 cells after beclin 1 siRNA or its negative control siRNA treatment. Red represents α-SMA; blue represents DAPI. (F) 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). (G) Collagen gel contraction assay was performed to detect the effect of beclin 1 siRNA and its negative control siRNA on the contractility of fibroblasts. (H and I) Proliferation of MRC-5 cells transfected with beclin 1 siRNA and its negative control siRNA, as assessed by EdU assays. Data are shown as the mean ± SEM (n = 3 in each group). (J) CCK8 assays were performed to evaluate cell proliferative ability in fibroblasts. Data are shown as the mean ± SEM (n = 3 in each group). Scale bar: 50 μm (E and H). P values were from (A) a 2-tailed unpaired Student’s t test and (C, D, F, I, and J) a 1-way ANOVA post hoc test with Tukey’s correction.

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