The miR-15a-5p-XIST-CUL3 regulatory axis is important for sepsis-induced acute kidney injury

• Published in: Renal failure Vol. 41; no. 1; pp. 955 - 966
• Main Authors: Xu, Guanhua, Mo, Lujiao, Wu, Channi, Shen, Xiaoyuan, Dong, Hongliang, Yu, Lingfeng, Pan, Ping, Pan, Kanda
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2019; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute kidney injury; Acute Kidney Injury - genetics; Adult; AKT protein; Animals; Apoptosis; Apoptosis - genetics; Cell Line; Cell Survival - genetics; Cell viability; Chromosome 5; competing endogenous RNA; Cullin; Cullin Proteins - genetics; Datasets as Topic; differentially expressed miRNAs; DNA microarrays; Down-Regulation; enrichment analysis; Female; Gene expression; Gene Expression Profiling; Gene Regulatory Networks - immunology; Humans; Kidneys; Laboratory Study; Lipopolysaccharides; Lipopolysaccharides - toxicity; Male; Mice; MicroRNAs - antagonists & inhibitors; MicroRNAs - metabolism; Middle Aged; miRNA; Oligonucleotide Array Sequence Analysis; Podocytes; Protein interaction; Protein Interaction Mapping; Protein Interaction Maps - genetics; regulatory network analysis; Renal function; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Small Interfering - metabolism; Sepsis; Sepsis - complications; Sepsis - genetics; Sepsis - immunology; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; siRNA; TOR protein; Transfection; Up-Regulation; competing endogenous RNA; regulatory network analysis; Acute kidney injury; differentially expressed miRNAs; enrichment analysis
• ISSN: 0886-022X; 1525-6049
• DOI: 10.1080/0886022X.2019.1669460

Background: Acute kidney injury (AKI) refers to a sudden loss of renal function. This study was performed to identify the key RNAs acting in the mechanism of sepsis-induced AKI. Methods: Microarray dataset GSE94717 (including six sepsis-induced AKI samples and three control samples) was downloaded from Gene Expression Omnibus database. Differentially expressed miRNAs (DE-miRNAs) were identified. The miRNA targets were predicted and enrichment analysis was performed. Protein-protein interaction (PPI) and competing endogenous RNA (ceRNA) regulatory networks were constructed. Mouse podocytes were treated with lipopolysaccharide (LPS), following by cell viability and PCR analysis. Cellular apoptosis and the ceRNA network were validated. Results: Thirty-one common DE-miRNAs (two up-regulated and 29 down-regulated) by AKI versus control and male AKI versus control were identified. We found the targets of miR-15a-5p, miR-15b-5p, and miR-16-5p were involved in mTOR signaling pathway, and those of miR-29b-3p and miR-16-5p were enriched in PI3K-Akt signaling pathway. RNAs including miR-15b-5p, miR-15a-5p, miR-107, XIST, miR-16-5p, and cullin 3 gene (CUL3) were included in the ceRNA regulatory network. The downregulation of miR-15a-5p and miR-15b-5p and the upregulation of lncRNA XIST and CUL3 gene were validated using qPCR. The miR-15a-5p-XIST-CUL3 regulatory axis was identified and was validated. We confirmed that LPS inhibited the growth of mouse podocytes and seven of the ten miRNAs, but upregulated XIST and CUL3. Transfection analysis showed XIST siRNA enhanced LPS-induced MPC5 cell apoptosis and miR-15a-5p inhibitor reserved it, so did as CUL3 overexpression for miR-15a-5p mimics. Conclusion: The miR-15a-5p-XIST-CUL3 regulatory axis was related to the pathogenesis of sepsis-induced AKI. Highlights Totally, 31 miRNAs were dysregulated between disease and control groups. MiR-15a-5p, miR-15b-5p, and miR-16-5p were involved in mTOR signaling pathway. MiR-16-5p and miR-29b-3p were implicated in PI3K-Akt signaling pathway. The miR-15a-5p-XIST-CUL3 axis was critical for sepsis-induced AKI.