MiR-9-5p protects from kidney fibrosis by metabolic reprogramming
MiR-9-5p protects from kidney fibrosis by metabolic reprogramming
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DOI：
10.1096/fj.201901599rr
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发表时间：
2020-01-01
期刊：
影响因子：
4.8
通讯作者：
Lamas, Santiago
中科院分区：
文献类型：
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作者：
Fierro-Fernandez, Marta;Miguel, Veronica;Lamas, Santiago
微小RNA（miRNAs）在转录后调节基因表达并控制生物学过程（BP），包括纤维化。肾纤维化仍然是一个临床挑战，miRNA可能代表一个有效的治疗途径。我们发现miR-9- 5 p在单侧输尿管梗阻（UUO）小鼠模型中保护肾纤维化。这反映在促纤维化标志物的表达减少、浸润单核细胞/巨噬细胞数量减少、肾小管上皮细胞损伤减少和人肾近端肾小管（HKC-8）细胞中转化生长因子-β 1（TGF-β 1）依赖性去分化。UUO模型中的RNA测序（RNA-Seq）研究显示，miR-9- 5 p处理可防止与关键代谢途径相关的基因下调，包括线粒体功能、氧化磷酸化（OXPHOS）、脂肪酸氧化（FAO）和糖酵解。在人肾小管上皮细胞中的研究表明，miR-9- 5 p阻止TGF-β 1诱导的生物能量学紊乱。FAO相关轴过氧化物酶体增殖物激活受体γ辅激活因子1 α（PGC-1 α）-过氧化物酶体增殖物激活受体α（PPAR α）的表达被UUO降低，尽管通过miR-9- 5 p的施用而得以保留。我们发现，在线粒体主调节因子PGC-1 α缺失的小鼠中，miR-9- 5 p无法促进UUO模型的保护作用。我们认为miR-9- 5 p通过诱导影响肾小管上皮细胞的代谢紊乱和线粒体功能障碍的重编程来增强对慢性肾损伤和肾纤维化的保护性反应。
MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-beta 1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-beta 1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha)-peroxisome proliferator-activated receptor alpha (PPAR alpha) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1 alpha, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.