MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways.
MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways.
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DOI：
10.1126/scitranslmed.3003205
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发表时间：
2012-02-15
影响因子：
17.1
通讯作者：
Duffield JS
中科院分区：
文献类型：
--
作者：
Chau BN;Xin C;Hartner J;Ren S;Castano AP;Linn G;Li J;Tran PT;Kaimal V;Huang X;Chang AN;Li S;Kalra A;Grafals M;Portilla D;MacKenna DA;Orkin SH;Duffield JS
肾脏瘢痕是一个主要的公共卫生问题，直接促进肾功能的丧失。为了了解microRNA（miRNA）在损伤后肾瘢痕形成过程中的作用，我们研究了两种肾纤维化模型中miRNA表达的变化，并鉴定了24种常见的上调miRNA。其中，miR-21在动物模型和人移植肾肾病中均高度升高。小鼠中miR-21的缺失未导致明显异常。然而，miR-21-/-小鼠对肾损伤的间质纤维化反应要少得多，这在用抗miR-21寡核苷酸处理的野生型小鼠中是表型复制的。令人惊讶的是，miR-21靶信使RNA的整体去抑制仅在损伤后的miR-21-/-肾中容易检测到。基因表达谱分析确定了参与代谢途径的基因组，这些基因在不存在miR-21的情况下上调，包括由过氧化物酶体增殖物激活受体-α（Pparα）（一种直接miR-21靶标）调节的脂质代谢途径。Pparα的过表达可防止UUO诱导的损伤和纤维化。Pparα缺乏消除了抗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Mpv 17 l被miR-21抑制，与增强的氧化性肾损伤密切相关。这些研究表明，miR-21在两种小鼠模型中有助于肾脏中的纤维发生和上皮损伤，并且是抗纤维化疗法的候选靶标。
Scarring of the kidney is a major public health concern, directly promoting loss of kidney function. In order 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 upregulated miRNAs. Among them, miR-21 was highly elevated in both animal models and human transplant kidney 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, which was pheno-copied in wild-type mice treated with anti-miR-21 oligonucleotides. Surprisingly, global de-repression of miR-21 target messenger RNAs was only readily detectable in miR-21-/- kidneys after injury. Analysis of gene expression profiles identified groups of genes involved in metabolic pathways that were up-regulated in the absence of miR-21, including the lipid metabolism pathway regulated by Peroxisome proliferator activated receptor-α (Pparα), a direct miR-21 target. Over-expression of Pparα prevented UUO-induced injury and fibrosis. Pparα deficiency abrogated the anti-fibrotic effect of anti-miR21 oligonucleotides. miR-21 also regulates 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 anti-fibrotic therapies.
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活性氧/氧化应激导致小鼠短暂缺血损伤后肾脏纤维化恶化
DOI：
10.1152/ajprenal.90735.2008
发表时间：
2009-08-01
影响因子：
4.2
作者：
Kim, Jinu;Seok, Young Mi;Park, Kwon Moo
通讯作者：
Park, Kwon Moo
DOI：
10.1016/j.bbrc.2006.04.008
发表时间：
2006-06-09
影响因子：
3.1
作者：
Iida, Reiko;Yasuda, Toshihiro;Kishi, Koichiro
通讯作者：
Kishi, Koichiro
影响因子：
6
作者：
Binder, CJ;Weiher, H;Kerjaschki, D
通讯作者：
Kerjaschki, D
影响因子：
29
作者：
Finck, BN;Bernal-Mizrachi, C;Kelly, DP
通讯作者：
Kelly, DP
影响因子：
3.5
作者：
KALDI, K;DIESTELKOTTER, P;JUST, WW
通讯作者：
JUST, WW