SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling

Sepsis-associated acute kidney injury (SA-AKI) is one of common critical illnesses with high morbidity and mortality. At present, effective therapeutic drugs for SA-AKI are remain lacking. SKLB023 is a synthetic small-molecule compound which exerts potent anti-inflammatory effects in our previous studies. Here, this study aimed to characterize the protective effect of SKLB023 on SA-AKI and explore its underlying mechanism. The SA-AKI experimental models have been established by cecum ligation/puncture (CLP) and lipopolysaccharide (LPS) injection in male C57BL/6J mice. SKLB023 was administered by gavage (50 or 25 mg/kg in CLP model and 50 mg/kg in LPS model) daily 3 days in advance and 30 min earlier on the day of modeling. Our results confirmed SKLB023 treatment could improve the survival of SA-AKI mice and ameliorate renal pathological injury, inflammation, and apoptosis in the two types of septic AKI mice. Mechanically, SKLB023 deceased the expression of TLR4 in LPS-triggered renal tubular epithelial cells, and inhibited the activation of downstream pathways including NF-κB and MAPK pathways. Our study suggested that SKLB023 is expected to be a potential drug for the prevention and treatment of septic AKI.