Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury

The contribution of miRNA to the pathogenesis of acute kidney injury (AKI) is not well understood. Here we evaluated an integrative network of miRNAs and mRNA data to discover a possible master regulator of AKI. Microarray analyses of the kidneys of mice treated with cisplatin were used to extract p...

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Bibliographic Details
Published in:Kidney international 2014-11, Vol.86 (5), p.943-953
Main Authors: Lee, Chan Gyu, Kim, Jin Geol, Kim, Hyun Joo, Kwon, Hyuk-Kwon, Cho, Il Je, Choi, Dal Woong, Lee, Woo Hyung, Kim, Won Dong, Hwang, Se Jin, Choi, Sangdun, Kim, Sang Geon
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Acetylation
acute kidney injury
Acute Kidney Injury - chemically induced
Acute Kidney Injury - genetics
Acute Kidney Injury - metabolism
Acute Kidney Injury - pathology
Animals
Binding Sites
Cell Death
Cisplatin
Computational Biology
Databases, Genetic
Disease Models, Animal
Forkhead Box Protein O3
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Gene Expression Profiling - methods
Gene Expression Regulation
Gene Regulatory Networks
Kidney Tubules - metabolism
Kidney Tubules - pathology
Male
Mice, Inbred C57BL
microarray analysis
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA expression
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
pathophysiology of renal disease
progression
Signal Transduction
Sirtuin 1 - genetics
Sirtuin 1 - metabolism
Time Factors
Transcriptome
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:The contribution of miRNA to the pathogenesis of acute kidney injury (AKI) is not well understood. Here we evaluated an integrative network of miRNAs and mRNA data to discover a possible master regulator of AKI. Microarray analyses of the kidneys of mice treated with cisplatin were used to extract putative miRNAs that cause renal injury. Of them, miR-122 was mostly downregulated by cisplatin, whereas miR-34a was upregulated. A network integrating dysregulated miRNAs and altered mRNA expression along with target prediction enabled us to identify Foxo3 as a core protein to activate p53. The miR-122 inhibited Foxo3 translation as assessed using an miR mimic, an inhibitor, and a Foxo3 3′-UTR reporter. In a mouse model, Foxo3 levels paralleled the degree of tubular injury. The role of decreased miR-122 in inducing Foxo3 during AKI was strengthened by the ability of the miR-122 mimic or inhibitor to replicate results. Increase in miR-34a also promoted the acetylation of Foxo3 by repressing Sirt1. Consistently, cisplatin facilitated the binding of Foxo3 and p53 for activation, which depended not only on decreased miR-122 but also on increased miR-34a. Other nephrotoxicants had similar effects. Among targets of p53, Phlda3 was robustly induced by cisplatin, causing tubular injury. Consistently, treatment with miR mimics and/or inhibitors, or with Foxo3 and Phlda3 siRNAs, modulated apoptosis. Thus, our results uncovered an miR integrative network regulating toxicant-induced AKI and identified Foxo3 as a bridge molecule to the p53 pathway.
ISSN:0085-2538
1523-1755
DOI:10.1038/ki.2014.117