MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells
MicroRNA-130b Ameliorates Murine Lupus Nephritis Through Targeting the Type I Interferon Pathway on Renal Mesangial Cells
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MicroRNA-130b 通过靶向肾系膜细胞上的 I 型干扰素途径改善小鼠狼疮性肾炎
DOI：
10.1002/art.39725
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发表时间：
2016-09-01
影响因子：
13.3
通讯作者：
Shen, Nan
中科院分区：
文献类型：
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作者：
Han, Xiao;Wang, Yan;Shen, Nan
目标。I型干扰素是狼疮性肾炎(LN)发生发展过程中的重要致病因子。虽然已经证明microRNAs(MiRNAs)可以控制LN免疫细胞中的干扰素反应，但miRNAs在常驻肾细胞中的作用尚不清楚。本研究旨在探讨microRNA-130b(miR-130b)在肾细胞干扰素途径中的作用及其对狼疮肾炎的治疗作用。收集患者和(NZB×NZW)F1狼疮易感小鼠肾组织，检测miR-130b水平。采用原代肾小球系膜细胞(RMC)检测miR-130b在干扰素途径中的作用。在干扰素加速的狼疮性肾炎小鼠模型中，通过给予miR-130b琼脂糖凝胶过表达miR-130b，以检验其治疗效果。在患者和狼疮易感小鼠的肾组织中观察到miR-130b表达下调。进一步分析表明，在LN患者中，miR-130b的低表达与干扰素反应的异常激活呈负相关。在体外，过表达miR-130b通过靶向干扰素调节因子1(IRF-1)来抑制RMC中I型干扰素途径下游的信号。抑制内源性miR-130b的表达则有相反的作用。在LN患者的肾活检标本中检测到IRF1和miR-130b水平呈负相关。更重要的是，体内应用miR-130b Agomir减少了干扰素加速的LN进展，减少了蛋白尿，降低了免疫复合体沉积水平，并减少了肾小球病变。MicroRNA-130b是一种新型的肾细胞I型干扰素途径负调控因子。在体内过表达miR-130b可以改善干扰素加速的LN，为LN的治疗干预提供了潜在的新策略。
Objective. Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN.Methods. Kidney tissues from patients and (NZB x NZW)F1 lupus-prone mice were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in the IFN pathway. We overexpressed miR-130b by administering miR-130b agomir in a mouse model of IFN-accelerated LN to test its therapeutic efficacy.Results. Down-regulated miR-130b expression was observed in kidney tissues from patients and lupus-prone mice. Further analysis showed that underexpression of miR-130b correlated negatively with abnormal activation of the IFN response in LN patients. In vitro, overexpressing miR-130b suppressed signaling downstream from the type I IFN pathway in RMCs by targeting IFN regulatory factor 1 (IRF-1). The opposite effect was observed when endogenous miR-130b expression was inhibited. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsy samples from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFN-accelerated progression of LN, with decreased proteinuria, lower levels of immune complex deposition, and lack of glomerular lesions.Conclusion. MicroRNA-130b is a novel negative regulator of the type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFN-accelerated LN, providing potential novel strategies for therapeutic intervention in LN.