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

• Published in: Kidney international Vol. 86; no. 5; p. 943
• 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: Journal Article
• Language: English
• Published: United States 01-11-2014
• Subjects: 3' Untranslated Regions; Acetylation; 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; MicroRNAs - genetics; MicroRNAs - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Signal Transduction; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Time Factors; Transcriptome; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1523-1755
• DOI: 10.1038/ki.2014.117

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.