迷迭香酸对脓毒症急性肾损伤大鼠NF-κB和p38 MAPK信号通路的影响

Regulation of rosmarinic acid on NF-κB and p38 MAPK signaling pathways in rats with sepsis and acute kidney injury

为探究迷迭香酸(rosmarinic acid,RA)对脓毒症急性肾损伤大鼠的保护作用及其机制,采用盲肠结扎穿孔术(cecal ligation and puncture,CLP)构建脓毒症肾损伤模型。将大鼠随机分为假手术组、模型组、RA 12.5 mg/kg组、RA 25 mg/kg组、RA 50 mg/kg组及地塞米松(dexamethasone,Dex;1 mg/kg)组,对比各组大鼠肾组织H-E染色结果、肾功能指标、氧化应激指标、肾组织细胞凋亡情况、NF-κB和p38 MAPK信号通路蛋白表达水平。结果显示,与模型组比较,RA 25 mg/kg组、RA 50 mg/kg组和Dex组血清肌酐(serum creatinine,Scr)、血尿素氮(blood urea nitrogen,BUN)、中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin,NGAL)、肾损伤分子1(kidney injury molecule 1,KIM-1)、TNF-α、IL-1β、IL-6、丙二醛(malondialdehyde,MDA)、肾组织凋亡细胞数、切割后(cleaved)Caspase-3/Caspase-3、细胞色素c(cytochrome c,Cyt c)、切割后聚腺苷二磷酸核糖聚合酶[cleaved poly(ADP-ribose)polymerase,cleaved PARP]、磷酸化p65(phosphorylated p65,p-p65)/p65及磷酸化p38(phosphorylated p38,p-p38)/p38水平显著降低(P<0.05),超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)水平显著升高(P<0.05),RA 50 mg/kg组和Dex组改善更为显著(P<0.05)。该研究提示,RA可抑制NF-κB和p38 MAPK信号通路,减轻炎症反应和氧化应激,降低肾组织细胞凋亡,从而改善脓毒症急性肾损伤。

The aim of this study is to explore the protective effect and mechanism of rosmarinic acid(RA)on rats with sepsis and acute kidney injury.The kidney injury models of sepsis were constructed by cecal ligation and puncture(CLP)and the rats were randomly divided into sham operation group,model group,RA groups(12.5,25,50 mg/kg),and dexamethasone(Dex,1 mg/kg)group.H-E staining of kidney tissues,renal function indexes,oxidative stress indexes,apoptosis of kidney tissues,and expressions of NF-κB and p38 MAPK signaling pathway proteins were compared among the groups.The results showed that compared to the model group,the RA groups(25,50 mg/kg)and Dex group had significantly decreased levels of serum creatinine(Scr),blood urea nitrogen(BUN),neutrophil gelatinase-associated lipocalin(NGAL),kidney injury molecule 1(KIM-1),TNF-α,IL-1β,IL-6,malondialdehyde(MDA),number of apoptosis cells in kidney tissues,cleaved Caspase-3/Caspase-3,cytochrome c(Cyt c),cleaved poly(ADP-ribose)polymerase(cleaved PARP),phosphorylated p65(p-p65)/p65 and phosphorylated p38(p-p38)/p38(P<0.05).In contrast,the levels of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)were significantly increased in RA groups(25,50 mg/kg)and Dex group(P<0.05).In addition,the improvement of the above indexes was more significant in RA group(50 mg/kg)and Dex group(P<0.05).The study suggests that RA inhibits NF-κB and p38 MAPK signaling pathways,alleviates inflammation response and oxidative stress,and reduces apoptosis of kidney tissues to improve sepsis and acute kidney injury.