Identification of microRNA-mRNA networks involved in cisplatin-induced renal tubular epithelial cells injury.

ABSTRACT

Cisplatin is a widely used chemotherapeutic drug that often causes acute kidney injury (AKI) in cancer patients. The contribution of miRNAs to the cisplatin-induced renal tubular epithelial cell injury remains largely unknown. Here we performed an integrative network analysis of miRNA and mRNA expression profiles to shed light into the underlying mechanism of cisplatin-induced renal tubular epithelial cell injury. Microarray analysis identified 47 differentially expressed miRNAs, among them 26 were upregulated and 21 were downregulated. Moreover, integrating dysregulated miRNAs target prediction and altered mRNA expression enabled us to identify 1181 putative target genes for further bioinformatics analysis. Gene ontology (GO) analysis revealed that the putative target genes were involved in apoptosis process and regulation of transcription. Pathway analysis indicated that the top upregulated pathways included MAPK and p53 signaling pathway, while the top downregulated pathways were PI3K-Akt and Wnt signaling pathway. Further network analysis showed that MAPK signaling pathway and apoptosis with the highest degree were identified as core pathways, hsa-miR-9-3p and hsa-miR-371b-5p as the most critical miRNAs, and CASK, ASH1L, CDK6 etc. as hub target genes. In addition, the expression level change of selected five microRNAs (hsa-miR-4299, hsa-miR-297, hsa-miR-3135b, hsa-miR-9-3p, and hsa-miR-371b-5p) and two mRNAs( CASK and CDK6) were validated in cisplatin-induced HK-2 cells. Furthermore, a similar trend of expression level change was observed in NRK-52E cells by cisplatin treatment. Overall, our results provide the molecular basis and potential targets for the treatment of cisplatin-induced renal tubular cell injury.