Regulus Therapeutics, San Diego, CA 92121, USA.
Sci Transl Med. 2012 Feb 15;4(121):121ra18. doi: 10.1126/scitranslmed.3003205.
Scarring of the kidney is a major public health concern, directly promoting loss of kidney function. To understand the role of microRNA (miRNA) in the progression of kidney scarring in response to injury, we investigated changes in miRNA expression in two kidney fibrosis models and identified 24 commonly up-regulated miRNAs. Among them, miR-21 was highly elevated in both animal models and in human transplanted kidneys with nephropathy. Deletion of miR-21 in mice resulted in no overt abnormality. However, miR-21(-/-) mice suffered far less interstitial fibrosis in response to kidney injury, a phenotype duplicated in wild-type mice treated with anti-miR-21 oligonucleotides. Global derepression of miR-21 target mRNAs was readily detectable in miR-21(-/-) kidneys after injury. Analysis of gene expression profiles up-regulated in the absence of miR-21 identified groups of genes involved in metabolic pathways, including the lipid metabolism pathway regulated by peroxisome proliferator-activated receptor-α (Pparα), a direct miR-21 target. Overexpression of Pparα prevented ureteral obstruction-induced injury and fibrosis. Pparα deficiency abrogated the antifibrotic effect of anti-miR-21 oligonucleotides. miR-21 also regulated the redox metabolic pathway. The mitochondrial inhibitor of reactive oxygen species generation Mpv17l was repressed by miR-21, correlating closely with enhanced oxidative kidney damage. These studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney in two mouse models and is a candidate target for antifibrotic therapies.
肾脏瘢痕形成是一个主要的公共卫生关注点，它直接促进了肾功能的丧失。为了了解 microRNA（miRNA）在损伤后肾脏瘢痕形成中的作用，我们研究了两种肾脏纤维化模型中 miRNA 表达的变化，并鉴定出 24 个常见上调的 miRNA。其中，miR-21 在两种动物模型和患有肾病的人移植肾脏中均高度升高。在小鼠中删除 miR-21 并没有导致明显的异常。然而，miR-21(-/-) 小鼠在肾脏损伤后遭受的间质纤维化要少得多，这种表型在接受抗 miR-21 寡核苷酸治疗的野生型小鼠中也得到了复制。在 miR-21(-/-) 肾脏损伤后，很容易检测到 miR-21 靶基因的全局去抑制。在没有 miR-21 的情况下上调的基因表达谱分析确定了一组参与代谢途径的基因，包括受过氧化物酶体增殖物激活受体-α（Pparα）调节的脂质代谢途径，这是 miR-21 的直接靶基因。Pparα 的过表达可预防输尿管梗阻引起的损伤和纤维化。Pparα 缺乏会消除抗 miR-21 寡核苷酸的抗纤维化作用。miR-21 还调节氧化还原代谢途径。活性氧生成的线粒体抑制剂 Mpv17l 被 miR-21 抑制，与增强的氧化肾损伤密切相关。这些研究表明，miR-21 促进了两种小鼠模型中的肾脏纤维化和上皮损伤，是抗纤维化治疗的候选靶标。
