MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation
MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation
复制标题
MicroRNA-214通过破坏线粒体氧化磷酸化促进慢性肾病
DOI：
10.1016/j.kint.2018.12.028
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发表时间：
2019-06-01
影响因子：
19.6
通讯作者：
Zhang, Aihua
中科院分区：
文献类型：
--
作者：
Bai, Mi;Chen, Huimei;Zhang, Aihua
线粒体对于决定细胞的能量稳态和命运至关重要，线粒体功能障碍与慢性肾病 (CKD) 的发病机制有关。我们试图找出致病的线粒体 microRNA。对健康小鼠肾组织的微阵列筛选鉴定出 97 种富含线粒体部分的 microRNA。我们重点关注 microRNA-214-3p (miR-214)，因为与其他器官相比，肾脏中线粒体与细胞质表达的比例非常高。 CKD患者肾组织中miR-214的表达量高于健康对照者，且与蛋白尿和肾纤维化程度呈正相关。在由梗阻、缺血/再灌注和白蛋白超载诱导的 CKD 小鼠模型的肾脏中，miR-214 的表达也有所增加。近端小管特异性删除 miR-214 可减轻这些 CKD 模型中的细胞凋亡、炎症、纤维化和线粒体损伤。 miR-214 的药理抑制在 CKD 白蛋白超载模型中具有类似的作用。在体外，近端肾小管细胞系中过度表达 miR-214 会诱导细胞凋亡并破坏线粒体氧化磷酸化，而 miR-214 表达会因各种损伤而上调。线粒体基因 mt-Nd6 和 mt-Nd4l 被确定为 miR-214 在肾脏中的特异性靶标。总之，这些结果证明了 miR-214 通过破坏线粒体氧化磷酸化在 CKD 中发挥致病作用，并表明 miR-214 有可能作为 CKD 的治疗靶点和诊断生物标志物。
Mitochondria are critical in determining a cell's energy homeostasis and fate, and mitochondrial dysfunction has been implicated in the pathogenesis of chronic kidney disease (CKD). We sought to identify causative mitochondrial microRNAs. A microarray screen of kidney tissue from healthy mice identified 97 microRNAs that were enriched in the mitochondrial fraction. We focused on microRNA-214-3p (miR-214) because of a very high ratio of mitochondrial to cytoplasmic expression in the kidney compared to other organs. Tubular expression of miR-214 was more abundant in kidney tissue from patients with CKD than from healthy controls, and was positively correlated with the degree of proteinuria and kidney fibrosis. Expression of miR-214 was also increased in the kidney of mouse models of CKD induced by obstruction, ischemia/reperfusion, and albumin overload. Proximal tubule-specific deletion of miR-214 attenuated apoptosis, inflammation, fibrosis, and mitochondrial damage in these CKD models. Pharmacologic inhibition of miR-214 had a similar effect in the albumin overload model of CKD. In vitro, overexpressing miR-214 in proximal tubular cell lines induced apoptosis and disrupted mitochondrial oxidative phosphorylation, while miR-214 expression was upregulated in response to a variety of insults. The mitochondrial genes mt-Nd6 and mt-Nd4l were identified as the specific targets of miR-214 in the kidney. Together, these results demonstrate a pathogenic role of miR-214 in CKD through the disruption of mitochondrial oxidative phosphorylation, and suggest the potential for miR-214 to serve as a therapeutic target and diagnostic biomarker for CKD.