MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgA nephropathy
MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgA nephropathy
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DOI：
10.1038/ki.2013.469
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发表时间：
2014-03-01
影响因子：
19.6
通讯作者：
Liu, Zhihong
中科院分区：
文献类型：
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作者：
Bao, Hao;Chen, Hao;Liu, Zhihong
肾小球内皮细胞(GEnCs)参与了IgA肾病(IgAN)的肾损害。在这里，我们描述了体外培养的人肾小球系膜细胞经条件培养液处理后的microRNAs(MiRNAs)。肾小球内皮细胞增生症患者的肾小球组织中miR-223的表达水平在肾小球内皮增殖症患者的肾小球组织中也明显降低。系膜来源的IL-6导致miR-223水平降低。外源性miR-223抑制细胞增殖、ICAM-1表达和单核细胞黏附。核因子-kappaB和STAT3信号通路在激活过程中相互协作。MIR-223模拟物抑制p65和STAT3的核定位和DNA结合，但对上游分子的表达没有影响。相反，被确认为miR-223靶标的importin alpha4和alpha5(多用途核运输受体)负责p65和STAT3的核运输。Importinα4和α5 siRNA抑制p65和STAT3的核定位，阻止细胞增殖和单核细胞黏附。循环内皮细胞miR-223水平降低，并与临床病理参数有关。因此，miR-223下调通过上调IgAN中Importinα4和α5来促进肾小球内皮细胞的激活。监测循环内皮细胞miR-223的水平可能为评估IgAN的严重程度提供一种无创的方法。
Glomerular endothelial cells (GEnCs) contribute to renal injuries in IgA nephropathy (IgAN). Here we profiled microRNAs (miRNAs) in GEnCs treated with conditioned medium from human mesangial cells in vitro. Levels of miR-223 in GEnCs decreased after incubation with the medium prepared with pIgA from patients with glomerular endothelial proliferation and were also decreased in the glomerular tissues of patients with glomerular endothelial proliferation. Mesangial-derived IL-6 caused miR-223 levels to decrease. The addition of exogenous miR-223 inhibited cell proliferation, ICAM-1 expression, and monocyte adhesion. The NF-kappa B and STAT3 signaling pathways collaborate during the activation process. MiR-223 mimics inhibited the nuclear localization and DNA binding of p65 and STAT3 but had no effect on the expression of upstream molecules. Instead, importin alpha 4 and alpha 5 (multipurpose nuclear transport receptors), validated as targets of miR-223, were responsible for the nuclear transport of p65 and STAT3. Importin alpha 4 and alpha 5 siRNA inhibited the nuclear localization of p65 and STAT3 and prevented cell proliferation and monocyte adhesion. The level of miR-223 in circulating endothelial cells was decreased and related to the clinical and pathological parameters. Thus, miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin alpha 4 and alpha 5 in IgAN. Monitoring the level of miR-223 in circulating endothelial cells may provide a noninvasive method for evaluating the severity of IgAN.