Integrative analysis of renal microRNA and mRNA to identify hub genes and pivotal pathways associated with Cyclosporine-induced acute kidney injury in mice

Cyclosporine (CsA) is widely used immunosuppressive drug that often causes acute kidney injury (AKI) in children. The exact molecular and cellular mechanisms underlying CsA-induced AKI remains largely unknown. Here we conducted an integrative network analysis of microRNAs (miRNAs) and mRNAs expression profiles to shed light into the underlying mechanisms of CsA-induced AKI. Small RNA-sequence analysis identified 25 differentially expressed miRNAs (DEMs) and RNA-sequence analysis identified 4109 differentially expressed mRNAs(DEGs).Subsequently, integrating DEMs target prediction and DEGs enabled us to identify 971 putative target genes for further bioinformatics analysis. Protein-protein interaction (PPI) analysis of 971 putative target genes was conducted based on string database and PPI network was visualized by Cytoscape software. Hub genes as well as key modules recognition were performed via CytoHubba plugin. Finally, 30 hub genes and 2 key modules are recognized via Protein-protein interaction analysis of 971 putative target genes. Functional enrichment analysis of 30 hub genes implied that inflammation and epithelial-mesenchymal transition (EMT)-related genes were primarily enriched. Pathway analysis identified that PI3K-Akt signaling pathway play a pivotal role in CsA-induced AKI. Network analysis showed that mmu-miR-17-5p, mmu-miR-19b-3p, mmu-miR-423-5p are the top miRNAs with highest degree from miRNA-mRNA regulatory network. Furthermore, the trend of expression change of mmu-miR-17-5p, mmu-miR-19b-3p, mmu-miR-423-5p in real-time PCR data were consistent with small RNA-sequence data. Overall, our study uncovers the pathogenic molecules and pathways promoting CsA-induced AKI from an integrative bioinformatics aspect and may pave a new way for understanding mechanism of CsA-induced AKI, which is beneficial for the discovery of novel targets for gene therapy and drug development.