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

Chan Gyu Lee, Jin Geol Kim, Hyun Joo Kim, Hyuk Kwon Kwon, Il Je Cho, DalWoong Choi, Woo Hyung Lee, Won Dong Kim, Se Jin Hwang, Sangdun Choi, Sang Geon Kim

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)943-953
Number of pages11
JournalKidney International
Volume86
Issue number5
DOIs
Publication statusPublished - 2014 Jan 1

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MicroRNAs
Acute Kidney Injury
Cisplatin
Wounds and Injuries
Kidney
Messenger RNA
3' Untranslated Regions
Microarray Analysis
Acetylation
Down-Regulation
Apoptosis
Proteins

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Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury. / Lee, Chan Gyu; Kim, Jin Geol; Kim, Hyun Joo; Kwon, Hyuk Kwon; Cho, Il Je; Choi, DalWoong; Lee, Woo Hyung; Kim, Won Dong; Hwang, Se Jin; Choi, Sangdun; Kim, Sang Geon.

In: Kidney International, Vol. 86, No. 5, 01.01.2014, p. 943-953.

Research output: Contribution to journalArticle

Lee, CG, Kim, JG, Kim, HJ, Kwon, HK, Cho, IJ, Choi, D, Lee, WH, Kim, WD, Hwang, SJ, Choi, S & Kim, SG 2014, 'Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury', Kidney International, vol. 86, no. 5, pp. 943-953. https://doi.org/10.1038/ki.2014.117
Lee, Chan Gyu ; Kim, Jin Geol ; Kim, Hyun Joo ; Kwon, Hyuk Kwon ; Cho, Il Je ; Choi, DalWoong ; Lee, Woo Hyung ; Kim, Won Dong ; Hwang, Se Jin ; Choi, Sangdun ; Kim, Sang Geon. / Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury. In: Kidney International. 2014 ; Vol. 86, No. 5. pp. 943-953.
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AU - Choi, DalWoong

AU - Lee, Woo Hyung

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AB - 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.

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