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

Kidney Int. 2014 Nov;86(5):943-53. doi: 10.1038/ki.2014.117. Epub 2014 Apr 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • 3' Untranslated Regions
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • Mirn122 microRNA, mouse
  • Nuclear Proteins
  • TSSC3 protein
  • Tumor Suppressor Protein p53
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Cisplatin