Analysis of dapagliflozin-induced expression profile of long noncoding RNAs in proximal tubular epithelial cells of diabetic kidney disease

Abstract

Abstract Background Accumulating evidence indicates that long noncoding RNAs (lncRNAs) play an important role in diabetic kidney disease (DKD). Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, exerts protective effects against DKD, but the underlying mechanism remains unclear. Methods In this study, we performed RNA microarray analysis to investigate differentially expressed lncRNAs and mRNAs in human proximal tubular epithelial cells (HK-2 cells) cultured with normal glucose (Ng), high glucose (Hg), and Hg plus DAPA, and conducted bioinformatic analyses to investigate their functions. Results Compared with the Ng group, 6761 lncRNAs and 3162 mRNAs were differentially expressed in the Hg group. Expression levels of 714 and 259 lncRNAs were up- and down-regulated, respectively, whereas those of 138 and 127 mRNAs were up- and down-regulated, respectively, after DAPA treatment (fold change ≥2, P < 0.05). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to assess the biological functions of lncRNAs and potential target genes. According to GO analysis, dysregulated mRNAs were primarily enriched in the cell cycle, whereas DAPA-induced mRNAs were enriched in collagen biosynthesis and regulation of programmed cell death. Type I diabetes mellitus and cell cycle signaling were the main KEGG pathways in the Hg group. However, cancer and signal transduction pathways were related to DAPA treatment. Conclusions Finally, we established protein–protein interaction (PPI) networks, as well as lncRNA–mRNA and lncRNA–miRNA–mRNA networks, and identified five potentially important lncRNAs whose expression levels were altered by DAPA treatment. Our findings suggest that lncRNAs are potential targets for DKD treatment.