JAK抑制剂托法替布减轻糖尿病肾病炎症因子浸润的作用研究

Effect of Tofatib,a JAK Inhibitor,on reducing inflammatory factor infiltration in diabetic nephropathy

目的 探究JAK抑制剂托法替布对糖尿病肾病炎症反应的治疗作用。方法 取96只SD大鼠,24只作为正常对照组(CT组);72只随机平均分为各干预组:DN模型组(DN组),阿托伐他汀治疗组(DA组),JAK抑制剂托法替布治疗组(DJ组),每组各24只。各干预组构建DN大鼠模型。测量各组大鼠体重,检测空腹血糖(FBG)水平;ELISA检测尿液中Uα1-MG和UmALb水平,以及血清中血肌酐、尿素氮和C反应蛋白水平,以及TNF-α、IL-1、TGF-β、IL-6、IL-8等炎症因子的水平;检测肾脏组织中TNF-α、TGF-β和NF-κВmRNA表达水平。结果 与CT组比较,随着时间延长,DN组大鼠FBG水平逐渐降低(P<0.01),体重逐渐增加(P<0.01),尿液中Uα1-MG和UmALb的水平显著升高(P<0.01),血清中Scr、BUN和CRP水平显著升高(P<0.01),且血清中TNF-α、IL-1、TGF-β、IL-6、IL-8炎症因子的水平升高(P<0.01),肾脏中TNF-α、TGF-β和NF-κВ的mRNA表达水平显著升高(P<0.01)。与DN组相比,DJ组整体状态良好,FBG水平升高(P<0.01),体重水平降低(P<0.01),尿液中Uα1-MG和UmALb的水平显著下降(P<0.01),血清中Scr、BUN和CRP水平显著降低(P<0.01),且血清中TNF-α、IL-1、TGF-β、IL-6、IL-8炎症因子的水平下降(P<0.01),肾脏中TNF-α、TGF-β和NF-κВ的mRNA表达水平显著降低(P<0.01),DJ组与DA组无显著差异(P>0.01)。结论 JAK抑制剂托法替布能通过降低DN大鼠免疫因子的水平改善DN大鼠的肾功能,相关研究成果将为临床DN的防治提供新的思路和应用依据。

Objective To investigate the therapeutic effect of Tofacitinib,a JAK inhibitor,on the inflammatory response in diabetic nephropathy.Methods 96 SD rats participated in the study,24 were used as normal control group(CT group)and 72 were randomly and equally divided into intervention groups:DN model group(DN group),atorvastatin treatment group(DA group)and JAK inhibitor Tofacitinib treatment group(DJ group),24 rats in each group.DN rat models were constructed in each intervention group.Body weight was measured and fasting blood glucose(FBG)levels were measured in each group;the levels of Uα1-MG and UmALb in urine,and the levels of blood creatinine,urea nitrogen and C-reactive protein in serum,as well as the levels of inflammatory factors such as TNF-a,IL-1,TGF-β,IL-6 and IL-8 were measured by ELISA;the levels of TNF-a,TGF-βand NF-κВmRNA in kidney tissues were measured.Results Compared with the CT group,with the extension of time,the rats in the DN group showed a gradual decrease in FBG levels(P<0.01),a gradual increase in body weight(P<0.01),a significant increase in the levels of Uα1-MG and UmALb in urine(P<0.01),and a significant increase in the serum levels of Scr,BUN and CRP levels were significantly increased(P<0.01),and the levels of TNF-a,IL-1,TGF-β,IL-6 and IL-8 inflammatory factors in serum were increased(P<0.01),and the mRNA expression levels of TNF-a,TGF-βand NF-κВin the kidney were significantly increased(P<0.01).Compared to the DN group,the DJ group was in good overall condition with increased FBG levels(P<0.01),decreased body weight levels(P<0.01),significantly decreased urinary levels of Uα1-MG and UmALb(P<0.01),significantly serum levels of Scr,BUN and CRP The levels of TNF-a,IL-1,TGF-β,IL-6 and IL-8 inflammatory factors in serum were reduced(P<0.01)and the mRNA expression levels of TNF-a,TGF-βand NF-κВin the kidney were significantly reduced(P<0.01),with no significant difference between the DJ and DA groups.Conclusions The JAK inhibitor Tofacitinib can improve the renal function of DN rats by decreasing the level of immune factors in DN rats,and the research results will provide a new idea and application basis for the prevention and treatment of DN in clinic.