Dapagliflozin impairs renal epithelial innate immunity and facilitates uropathogenic E. coli infection in diabetes

Risk of pyelonephritis is very high among patients with diabetes. During diabetes, the oral antidiabetic drug, dapagliflozin (DAPA) is commonly prescribed for its well-recognized renoprotective effects. Although DAPA lowers renal glucose reabsorption, it significantly increases urinary glucose levels, which may raise the risk of lower urinary tract infections (UTIs). The molecular mechanisms underlying increased UTI susceptibility remain incompletely understood. Cytotoxicity assay, glucose uptake assay and uropathogenic E. coli (UPEC) adhesion, intracellular bacterial survival assays were evaluated in human renal epithelial cells, A498 and HK-2. Further, expression of cell membrane receptor proteins, antimicrobial peptide, tight junction protein, autophagic marker at transcriptional and translational levels were measured either using qRT-PCR, immunocytochemistry or western blotting respectively. Specific fluorescence-based dyes were used to measure the free radical species. Thereafter, publicly available in vivo RNAseq data was analyzed to identify the target of interest and confirmed in vitro. Atomic force microscopy was performed to measure the topological architecture of cells after DAPA treatment in human renal epithelial cells. In this study, we investigated the potential role of DAPA in promoting UTI by compromising the innate immune defense of human renal epithelial cells. Effects of DAPA were examined under both normal and high glucose conditions. Interestingly, under high glucose conditions, DAPA treatment resulted in increased expression of the cell membrane receptor protein, MRC1, cytoskeletal rearrangement, and reduced expression of antimicrobial peptide human β-defensin 1 and the tight junction protein, TJP1. These alterations favored an increased rate of infection by UPEC. Furthermore, DAPA mediated alterations in free radical regulation and autophagic pathways enhanced intracellular bacterial survival, supporting its immunomodulatory effects. In conclusion, our findings elucidate the mechanisms by which DAPA, under high glucose conditions, compromises innate immune defenses in renal epithelial cells, thereby increasing susceptibility to UPEC infection.