SENP2调控NLRP3炎症小体活化对脓毒症小鼠急性肾损伤中的保护作用  

Protective effect of SENP2 on acute kidney injury in septic mice by regulating NLRP3 inflammasome activation

作　　者：樊恒[1] 孙敏[1] 朱建华 Fan Heng;Sun Min;Zhu Jianhua(Department of Intensive Care Unit,The First Affi liated Hospital of Ningbo University,Ningbo 315010,China)

机构地区：[1]宁波大学附属第一医院重症医学科,宁波315010

出　　处：《中华急诊医学杂志》2025年第2期187-192,共6页Chinese Journal of Emergency Medicine

基　　金：宁波市自然科学基金重点项目(2022J202);浙江省自然科学基金华东医药企业创新发展联合基金资助项目(LHDMZ23H050001);浙江省医药卫生科技计划项目(2023KY251,2024KY312);宁波市重点研发计划暨“揭榜挂帅”项目(2023Z174);宁波市急危重症疾病临床研究中心(2024L003)。

摘　　要：目的研究小泛素样修饰蛋白特异性肽酶2(SENP2)调控NLRP3炎症小体活化对脓毒症小鼠急性肾损伤(AKI)中的保护作用。方法将40只C57BL/6小鼠分为4组,即野生型假手术组(WT-Sham)、野生型盲肠结扎和穿孔术组(WT-CLP)、SENP2基因敲除假手术组(KO-Sham)和SENP2基因敲除盲肠结扎和穿孔术组(KO-CLP),每组10只。观察各组小鼠肾组织病理损伤,使用ELISA法检测血肌酐(SCr)、血尿素氮(BUN)、血浆中性粒细胞明胶酶相关脂蛋白(pNGAL)和血浆肾损伤分子1(pKIM-1)水平,测定血浆TNF-α、IL-1β、IL-4和IL-10水平;采用免疫组织化学法检测肾组织SENP2蛋白表达,蛋白印迹法测定肾组织中NLRP3、IL-1β、Caspase-1和ASC蛋白表达。结果与WT-Sham组和KO-Sham组比较,WT-CLP组和KO-CLP组小鼠肾组织病理损伤评分以及血浆中SCr、BUN、pNGAL、pKIM-1、TNF-α和IL-1β的水平均显著升高(P均<0.001),而IL-4和IL-10水平均显著降低(P均<0.001),同时肾组织中NLRP3、IL-1β、Caspase-1和ASC蛋白水平均显著升高(P均<0.001)。与WT-CLP组比较,KO-CLP组小鼠肾组织损伤评分明显降低(P<0.01),SCr、BUN、pNGAL、pKIM-1、TNF-α和IL-1β水平均明显降低(P均<0.05),NLRP3[(0.71±0.04)vs.(0.89±0.01),P=0.011]、IL-1β[(0.41±0.02)vs.(0.57±0.01),P=0.004]、Caspase-1[(0.41±0.02)vs.(0.56±0.02),P=0.009]和ASC[(0.27±0.01)vs.(0.41±0.02),P=0.009]蛋白水平均显著降低。结论SENP2通过调控NLRP3炎症小体活化参与SAKI疾病的发生和发展。Objective To explore the protective effect of small ubiquitin-related moditier protein specific peptidase 2(SENP2)on acute kidney injury in septic mice by regulating NLRP3 inflammasome activation.Methods Forty C57BL/6 mice were divided into 4 groups:namely the wild-type sham group(WT-Sham),wild-type cecal ligation and perforation group(WT-CLP),SENP2 gene knockout sham group(KO-Sham),and SENP2 gene knockout cecal ligation and perforation group(KO-CLP),with 10 mice in each group.It was observed the pathological damage of kidney tissue in each group of mice,used ELISA method to detect blood creatinine(SCr),blood urea nitrogen(BUN),plasma neutrophil gelatinase related lipoprotein(pNGAL),and plasma kidney injury molecule 1(pKIM-1)levels,and determined plasma TNF-α,IL-1β,IL-4 and IL-10 levels.It was used immunohistochemical method to detect the expression of SENP2 protein in renal tissue,while used western-blotting to detect NLRP3,IL-1β,Caspase-1 and ASC protein expression in renal tissue.Results Compared with the WT-Sham and KO-Sham groups,in the WT-CLP and KO-CLP groups,the pathological damage scores of the kidney tissue and the levels of SCr,BUN,pNGAL,pKIM-1,TNF-αand IL-1βin plasma were all signifi cantly increased(all P<0.001),while the levels of IL-4 and IL-10 were all significantly reduced(allP<0.001),and the levels of NLRP3,IL-1β,Caspase-1 and ASC proteins were all significantly increased(all P<0.001).Moreover,compared with the WT-CLP group,the KO-CLP group showed a significant decrease in renal tissue injury scores in mice(P˂0.01),the levels of SCr,BUN,pNGAL,pKIM-1,TNF-αand IL-1βwere all significantly reduced(allP<0.05),and the levels of NLRP3[(0.71±0.04)vs.(0.89±0.01),P=0.011],IL-1β[(0.41±0.02)vs.(0.57±0.01),P=0.004],Caspase-1[(0.41±0.02)vs.(0.56±0.02),P=0.009],and ASC[(0.27±0.01)vs.(0.41±0.02),P=0.009]were all significantly reduced.Conclusion SENP2 participates in the occurrence and development of septic AKI by regulating the activation of NLRP3 inflammasomes.

关 键 词：SENP2 脓毒症 急性肾损伤 NLRP3 炎症 

分 类 号：R459.7[医药卫生—急诊医学] R692[医药卫生—治疗学]