VX-702 Ameliorates the Severity of Sepsis-Associated Acute Kidney Injury by Downregulating Inflammatory Factors in Macrophages
Purpose: Sepsis-associated acute kidney injury (S-AKI) significantly increases mortality rates, yet there are no specific treatments available. This study aimed to investigate the mechanisms underlying S-AKI and identify potential therapeutic drugs to mitigate this condition.
Methods: We established a stable mouse model of S-AKI through incision infection with Pseudomonas aeruginosa. Using high-throughput sequencing and bioinformatics analysis, we explored the underlying mechanisms and selected VX-702 as a target drug for S-AKI. In an in vitro model, we co-cultured a kidney tubular epithelial cell line (TCMK-1) with lipopolysaccharide (LPS)-induced leukemic monocyte/macrophage cells (RAW264.7) to evaluate the effects of VX-702 on S-AKI.
Results: Our findings identified interleukin (IL)-6 and IL-1β as key hub genes, with the mitogen-activated protein kinase (MAPK) signaling pathway being the primary pathway involved in S-AKI. Oral administration of VX-702 significantly reduced elevated levels of IL-6, IL-1β, serum creatinine, and blood urea nitrogen in mice with S-AKI. Additionally, VX-702 decreased the number of apoptotic cells in damaged kidney tissues. In the co-culture system, TCMK-1 cells showed reduced viability and increased apoptosis when exposed to LPS-induced RAW264.7 cells, but these effects were reversed by VX-702 treatment. VX-702 also lowered levels of phosphorylated p38 MAPK and pro-inflammatory cytokines in RAW264.7 cells and their supernatants. Molecular docking studies indicated that VX-702 can bind to IL-6, IL-1β, and MAPK, influencing the interaction between IL-1β and its receptor.
Conclusion: VX-702 alleviated S-AKI by inhibiting the release of pro-inflammatory cytokines from macrophages, suggesting its potential as a novel therapeutic option for treating S-AKI.