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

Abstract:

: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.

journal_name

Kidney Int

journal_title

Kidney international

authors

Bai M,Chen H,Ding D,Song R,Lin J,Zhang Y,Guo Y,Chen S,Ding G,Zhang Y,Jia Z,Huang S,He JC,Yang L,Zhang A

doi

10.1016/j.kint.2018.12.028

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

1389-1404

issue

6

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(19)30114-0

journal_volume

95

pub_type

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