A microRNA-30e/mitochondrial uncoupling protein 2 axis mediates TGF-β1-induced tubular epithelial cell extracellular matrix production and kidney fibrosis.
A microRNA-30e/mitochondrial uncoupling protein 2 axis mediates TGF-β1-induced tubular epithelial cell extracellular matrix production and kidney fibrosis.
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DOI：
10.1038/ki.2013.80
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发表时间：
2013-08
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
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线粒体功能障碍已在各种肾脏疾病中报道，但它如何导致肾脏纤维化以及如何调节尚不清楚。在这里，我们发现，线粒体解偶联蛋白2（UCP 2）诱导肾小管上皮细胞在小鼠单侧输尿管梗阻后，与消融UCP 2的小鼠抵抗梗阻诱导的肾纤维化。我们在培养的NRK-52 E细胞中进一步测试了这种关联，发现TGF-β1显著诱导UCP 2表达。UCP 2的敲低在很大程度上消除了TGF-β1的作用，而UCP 2的过表达促进了肾小管细胞表型的改变。使用UCP 2 mRNA-3′-非翻译区荧光素酶构建体的分析表明，UCP 2 mRNA是miR-30 e的直接靶点。miR-30 e在纤维化肾小管细胞和TGF-β1处理的NRK-52 E细胞中下调。miR-30 e模拟物显著抑制TGF-β1诱导的肾小管细胞上皮-间质转化，而miR-30 e抑制剂模拟TGF-β1的作用。最后，京尼平，一种糖苷配基UCP 2抑制剂，显着改善小鼠肾纤维化。因此，miR-30 e/UCP 2轴在介导TGF-β1诱导的上皮-间质转化和肾纤维化中具有重要作用。靶向这一途径可能为纤维化肾病治疗的未来带来新的曙光。
Mitochondria dysfunction has been reported in various kidney diseases but how it leads to kidney fibrosis and how this is regulated is unknown. Here we found that mitochondrial uncoupling protein 2 (UCP2) was induced in kidney tubular epithelial cells after unilateral ureteral obstruction in mice and that mice with ablated UCP2 resisted obstruction-induced kidney fibrosis. We tested this association further in cultured NRK-52E cells and found that TGF-β1 remarkably induced UCP2 expression. Knockdown of UCP2 largely abolished the effect of TGF-β1, whereas overexpression of UCP2 promoted tubular cell phenotype changes. Analysis using a UCP2 mRNA-3′-untranslated region luciferase construct showed that UCP2 mRNA is a direct target of miR-30e. MiR-30e was downregulated in tubular cells from fibrotic kidneys and TGF-β1-treated NRK-52E cells. A miR-30e mimic significantly inhibited TGF-β1-induced tubular-cell epithelial–mesenchymal transition, whereas a miR-30e inhibitor imitated TGF-β1 effects. Finally, genipin, an aglycone UCP2 inhibitor, significantly ameliorated kidney fibrosis in mice. Thus, the miR-30e/UCP2 axis has an important role in mediating TGF-β1-induced epithelial–mesenchymal transition and kidney fibrosis. Targeting this pathway may shed new light for the future of fibrotic kidney disease therapy.
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影响因子：
30.8
作者：
Fleury, C;Neverova, M;Warden, CH
通讯作者：
Warden, CH
DOI：
10.1161/01.atv.0000153141.42033.22
发表时间：
2005-03-01
影响因子：
8.7
作者：
Oberkofler, H;Iglseder, B;Patsch, W
通讯作者：
Patsch, W
DOI：
10.1073/pnas.0403293101
发表时间：
2004-06-29
影响因子：
11.1
作者：
Liu, CG;Calin, GA;Croce, CM
通讯作者：
Croce, CM
影响因子：
4.8
作者：
NegreSalvayre, A;Hirtz, C;Casteilla, L
通讯作者：
Casteilla, L
影响因子：
--
作者：
BALABAN, RS;MANDEL, LJ
通讯作者：
MANDEL, LJ