MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation

被引：104

作者：

Bai, Mi ^{[1
,2
]}

Chen, Huimei ^{[3
]}

Ding, Dan ^{[1
,2
]}

Song, Ruihua ^{[1
,2
]}

Lin, Jiajuan ^{[1
,2
]}

Zhang, Yuanyuan ^{[1
,2
]}

Guo, Yan ^{[1
,2
]}

Chen, Shuang ^{[1
,2
]}

Ding, Guixia ^{[1
,2
]}

Zhang, Yue ^{[1
,2
]}

Jia, Zhanjun ^{[1
,2
]}

Huang, Songming ^{[1
,2
]}

He, John Cijiang ^{[4
]}

Yang, Li ^{[5
]}

Zhang, Aihua ^{[1
,2
]}

机构：

[1] Nanjing Med Univ, Childrens Hosp, State Key Lab Reprod Med, Dept Nephrol, 72 Guangzhou Rd, Nanjing 210029, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Jiangsu Key Lab Pediat, Nanjing, Jiangsu, Peoples R China

[3] Nanjing Univ, Sch Med, Jinling Hosp, Natl Clin Res Ctr Kidney Dis, Nanjing, Jiangsu, Peoples R China

[4] Icahn Sch Med Mt Sinai, Div Nephrol, Dept Med, New York, NY 10029 USA

[5] Peking Univ, Renal Div, Hosp 1, Beijing, Peoples R China

来源：

KIDNEY INTERNATIONAL | 2019年 / 95卷 / 06期

基金：

中国国家自然科学基金;

关键词：

chronic kidney disease; miR-214; mitochondrial OXPHOS; MOLECULAR-MECHANISMS; ALLOTOPIC EXPRESSION; PROXIMAL TUBULE; DYSFUNCTION; PROGRESSION; COMPLEX; GENOME; MUSCLE; INJURY; GENES;

D O I：

10.1016/j.kint.2018.12.028

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

100201 [内科学]; 100221 [泌尿外科学];

摘要：

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.

引用

页码：1389 / 1404

页数：16

共 40 条

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