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Updated: Apr 30, 2026
A Quantitative Detection Method for MicroRNAs in the Kidney of an Ischemic Kidney Injury Mouse Model
Published on: September 11, 2020
Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury
Chan Gyu Lee1, Jin Geol Kim1, Hyun Joo Kim1
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea.
Abstract:
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.
Insights
MicroRNAs (miRNAs) regulate toxicant-induced acute kidney injury (AKI) by controlling the Foxo3 protein. This pathway involves miR-122 and miR-34a, ultimately impacting the p53 pathway and tubular injury.
Area of Science:
- Molecular Biology
- Renal Physiology
- Toxicology
Background:
- The role of microRNAs (miRNAs) in acute kidney injury (AKI) pathogenesis remains unclear.
- Understanding miRNA-mRNA interactions is crucial for identifying key regulators of renal injury.
Purpose of the Study:
- To investigate an integrative network of miRNAs and mRNA to discover a master regulator of toxicant-induced AKI.
- To elucidate the specific roles of miR-122 and miR-34a in AKI and their connection to the p53 pathway.
Main Methods:
- Microarray analysis of cisplatin-treated mouse kidneys to identify dysregulated miRNAs and mRNAs.
- Integrative network analysis incorporating miRNA and mRNA expression data with target prediction.
- In vivo and in vitro experiments using miRNA mimics, inhibitors, and small interfering RNAs (siRNAs) to assess functional roles.
Main Results:
- Cisplatin treatment altered miR-122 (downregulated) and miR-34a (upregulated) levels in mouse kidneys.
- Foxo3 was identified as a core protein linking miRNAs to p53 activation; miR-122 inhibited Foxo3 translation, while miR-34a promoted Foxo3 acetylation by repressing Sirt1.
- Foxo3 levels correlated with tubular injury severity, and its interaction with p53 was modulated by both miR-122 and miR-34a.
- p53 target Phlda3 was induced by cisplatin, contributing to tubular injury, and modulating this pathway affected apoptosis.
Conclusions:
- An integrative miRNA-mRNA network regulates toxicant-induced AKI.
- Foxo3 acts as a critical bridge molecule connecting miRNA dysregulation to the p53 pathway activation in AKI.
- Targeting this miRNA-Foxo3-p53 axis offers potential therapeutic strategies for AKI.
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