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 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.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Chan Gyu
CG
Lee
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Jin Geol
JG
Kim
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Hyun Joo
HJ
Kim
Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
Hyuk-Kwon
HK
Kwon
College of Oriental Medicine, Daegu Haany University, Daegu, Korea.
Il Je
IJ
Cho
Department of Public Health Science, Graduate School, College of Health Sciences, Korea University, Seoul, Korea.
Dal Woong
DW
Choi
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Woo Hyung
WH
Lee
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Won Dong
WD
Kim
College of Medicine, Hanyang University, Seoul, Korea.
Se Jin
SJ
Hwang
Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
Sangdun
S
Choi
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Sang Geon
SG
Kim
D020413:3' Untranslated Regions; D000107:Acetylation; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001665:Binding Sites; D016923:Cell Death; D002945:Cisplatin; D019295:Computational Biology; D030541:Databases, Genetic; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D020413:3' Untranslated Regions; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D009687:Nuclear Proteins; C109277:TSSC3 protein; D016159:Tumor Suppressor Protein p53; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002945:Cisplatin