URB597 attenuates experimental sepsis-associated acute kidney injury with reduced renal inflammation, apoptosis, and TLR4/NF-κB activation.

BACKGROUND: The endocannabinoid system regulates inflammatory and apoptotic processes involved in sepsis-associated acute kidney injury (AKI). Fatty acid amide hydrolase (FAAH), a key enzyme responsible for anandamide degradation, may influence renal injury. This study investigated the protective effects of the FAAH inhibitor URB597 in cecal ligation and puncture (CLP)-induced sepsis-associated AKI. METHODS: Forty male Sprague-Dawley rats were allocated to four groups (n = 10/group): Control, CLP, CLP+URB597 0.3 mg/kg, and CLP+URB597 0.6 mg/kg. URB597 was administered intraperitoneally within 5 min after CLP. Serum and kidney samples were collected at 24 h for biochemical, histopathological, and immunohistochemical analyses. RESULTS: CLP significantly increased serum blood urea nitrogen (BUN), creatinine, neutrophil gelatinase-associated lipocalin (NGAL), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) levels and induced renal histopathological injury. Both URB597 doses significantly reduced these alterations compared with CLP (p < 0.05), with no significant differences between doses in serum biochemical parameters. URB597 also reduced CLP-induced renal immunoreactivity of Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-kappa B (p-NF-κB), phosphorylated IκB-α (p-IκB-α), TNF-α, IL-1β, interleukin-6 (IL-6), cleaved caspase-3, and caspase-8 (p < 0.05). CONCLUSIONS: URB597 attenuated renal injury, inflammatory responses, and apoptosis-related alterations in experimental sepsis-associated AKI. These effects were accompanied by reduced renal TLR4/NF-κB pathway activation.