Farnesoid X Receptor Alleviates Cisplatin-Induced Kidney Inflammatory Injury by Inhibiting Tlr4/NF-κB Pathway.

Inflammatory responses play a critical role in cisplatin-induced acute kidney injury (AKI). Farnesoid X receptor (FXR) has been shown to mitigate kidney dysfunction, but its mechanism remains unclear. This study aims to explore whether FXR reduces cisplatin-induced AKI by modulating inflammation. Using a mouse model of AKI, we demonstrated that cisplatin-induced obvious inflammation in the kidney, evidenced by increased macrophage and neutrophil infiltration, elevated expression of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), IL-6, C-X-C motif chemokine ligand (CXCL) 1, 2, 5, 20, and C-C motif chemokine ligand (CCL) 2, and activation of the toll-like receptor 4 (Tlr4)/nuclear factor-kappa B (NF-κB) pathway. RNA sequencing further corroborated these findings, revealing upregulation of inflammation-related genes and activation of several inflammatory pathways in the kidney after cisplatin administration. Pretreatment with GW4064 (a FXR agonist) reduced inflammatory cytokine expression, immune cell infiltration, and Tlr4/NF-κB activation, alleviating kidney injury. However, proximal tubule-specific FXR knockout worsened renal inflammation and increased NF-κB activity. In vitro, GW4064 decreased pro-inflammatory cytokine production, suppressed Tlr4/NF-κB signalling, and reduced apoptosis in cisplatin-treated renal tubular epithelial cells. Together, these findings demonstrate that FXR significantly alleviates cisplatin-induced renal inflammation via suppressing Tlr4/NF-κB signalling. FXR activation may represent a promising therapeutic strategy to mitigate cisplatin-induced AKI.