Department of Critical, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, PRChina.
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PRChina.
Ren Fail. 2024 Dec;46(1):2313176. doi: 10.1080/0886022X.2024.2313176. Epub 2024 Feb 15.
This study was designed to observe the effect of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway activity on sepsis-associated acute kidney injury (SA-AKI), thereby providing new considerations for the prevention and treatment of SA-AKI.
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-κB signaling pathway was observed by western blot.
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 ( < 0.01), as well as increased superoxide dismutase (SOD) activity of CLP rats ( < 0.01). Additionally, TAK-242 treatment improved the condition of CLP rats that had glomerular and tubular injuries and mitochondrial disorders ( < 0.01). Further mechanism research revealed that TAK-242 can inhibit the TLR4/NF-κB signaling pathway activated by CLP ( < 0.01). Above indicators after TAK-242 treatment were close to those of the Sham group.
TAK-242 can improve oxidative stress, mitochondrial dysfunction, and inflammatory response by inhibiting the activity of TLR4/NF-κB signaling pathway, thereby preventing rats from SA-AKI.
本研究旨在观察 Toll 样受体 4（TLR4）/核因子 kappa-B（NF-κB）通路活性对脓毒症相关性急性肾损伤（SA-AKI）的影响，为 SA-AKI 的防治提供新的思路。
将大鼠分为假手术（Sham）组、盲肠结扎穿孔（CLP）组、CLP+ vehicle 组和 CLP+ TAK-242 组。除 Sham 组外，其余各组均建立 CLP 诱导的脓毒症模型。24 h 后，检测各组大鼠血液样本中与肾损伤相关的指标。苏木精-伊红（HE）染色观察肾脏组织病理学变化，肾小管损伤评分；检测各组大鼠氧化应激相关因子、线粒体功能相关指标；酶联免疫吸附试验（ELISA）检测各组大鼠血清及肾组织中炎症因子水平；Western blot 检测 TLR4/NF-κB 信号通路相关蛋白的表达。
与 CLP+ vehicle 组和 CLP+ TAK-242 组比较，CLP+ TAK-242 组降低脓毒症大鼠的血尿素氮（BUN）、肌酐（Cr）、胱抑素-C（Cys-C）、活性氧（ROS）、丙二醛（MDA）及炎症因子水平（P<0.01），提高超氧化物歧化酶（SOD）活性（P<0.01）；TAK-242 治疗改善 CLP 大鼠肾小球和肾小管损伤及线粒体功能障碍（P<0.01）；进一步机制研究发现，TAK-242 可抑制 CLP 诱导的 TLR4/NF-κB 信号通路的激活（P<0.01）；TAK-242 治疗后各项指标接近 Sham 组。
TAK-242 通过抑制 TLR4/NF-κB 信号通路的活性，改善氧化应激、线粒体功能障碍及炎症反应，从而预防大鼠发生 SA-AKI。
