TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway
Yanmei Xia, Yu-qian Guan, Jifang Liang, Weidong Wu
Abstract
Objective: This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-B) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI.Methods: The rats were divided into Sham, cecal ligation and puncture (CLP), CLP + vehicle, and CLP + TAK-242 groups.Except the Sham group, a model of CLP-induced sepsis was established in other groups.After 24 h, the indicators related to kidney injury in blood samples were detected.The pathological changes in the kidneys were observed by hematoxylin-eosin staining, and tubular damage was scored.Oxidative stress-related factors, mitochondrial dysfunction-related indicators in each group were measured; the levels of inflammatory factors in serum and kidney tissue of rats were examined.Finally, the expression of proteins related to the TLR4/NF-B signaling pathway was observed by western blot.Results: Compared with the CLP + vehicle and CLP + TAK-242 groups, the CLP + TAK-242 group reduced blood urea nitrogen (BUN), creatinine (Cr), cystatin-C (Cys-C), reactive oxygen species (ROS), malondialdehyde (MDA), and inflammatory factors levels (p < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats (p < 0.01).Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders (p < 0.01).Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-B signaling pathway activated by CLP (p < 0.01).Above indicators after TAK-242 treatment were close to those of the Sham group.Conclusion: TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-B signaling pathway, thereby preventing rats from SA-AKI.