Comprehensive circRNA Expression Profile and Transcriptomics-Based Molecular Pathway Analysis of the Sodium-Glucose Co-Transporter-2 Inhibitor Dapagliflozin in Diabetic Tubular Epithelial Cells

Diabetic kidney disease (DKD) is a serious diabetes complication. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel anti-diabetes drugs and have clinical renal protection. However, the molecular mechanisms involved remain unclear. Here, human proximal tubular epithelial cells (PTECs) were treated with normal glucose (NG), high glucose (HG), and three types of anti-diabetes agents including SGLT2i (dapagliflozin), metformin, and dipeptidyl peptidase-4 inhibitor (DPP4i, vildagliptin) to perform microarray analysis. A total of 2,710 differentially expressed (DE) circRNAs were identified in PTECs. Network pharmacology, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the effects of dapagliflozin on PTECs primarily involved lipid metabolism, Rap1, and MAPK signaling pathways. The effects of metformin were mainly on the AMPK and FOXO signaling pathways, whereas vildagliptin were on insulin secretion and the HIF-1 signaling pathway. Furthermore, circRNA-miRNA-mRNA networks revealed that dapagliflozin might regulate the primary bile acid biosynthesis, arginine and proline metabolism, and vesicular transport through the hsa_circ_1586-miR-4739/hsa-miR-7851-3p/miR-1273g-3p networks, and regulate the MAPK, ErbB, and insulin resistance signaling pathways through the has_circ_012448-hsa-miR-378g/hsa-miR-29b-5p networks. Overall, our study elucidates circRNA expression profile in PTECs treated with dapagliflozin for the first time, providing novel clues for exploring the molecular mechanisms of dapagliflozin on DKD.