Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury
- 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
- Issue Date
- 11월-2014
- Publisher
- ELSEVIER SCIENCE INC
- Keywords
- acute kidney injury; cell death; microarray analysis; miRNA expression; pathophysiology of renal disease; progression
- Citation
- KIDNEY INTERNATIONAL, v.86, no.5, pp.943 - 953
- Indexed
- SCIE
SCOPUS
- Journal Title
- KIDNEY INTERNATIONAL
- Volume
- 86
- Number
- 5
- Start Page
- 943
- End Page
- 953
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/97026
- DOI
- 10.1038/ki.2014.117
- ISSN
- 0085-2538
- 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.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - College of Health Sciences > School of Health and Environmental Science > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.