IL-33调控JAK/STAT通路对狼疮肾炎肾小管损伤的影响

Effects of IL-33 on renal tubular injury in lupus nephritis through the JAK/STAT signaling pathway

目的 探讨白细胞介素33(IL-33)在狼疮性肾炎小鼠肾小管损伤中的作用及相关机制.方法 12周龄雌性MRL/lpr鼠作为狼疮性肾炎的模型小鼠,随机分为模型组、IL-33组和溶剂对照组,同龄雌性MRL/MP鼠作为正常对照组,每组各10只.IL-33组每次腹腔注射100μl含2μg重组鼠IL-33的磷酸盐缓冲液(PBS),每天一次,连续14d,对照组和模型组腹腔注射等量PBS液.14周龄时处死小鼠,分离血清检测肌酐(Cr)、尿素氮(BUN)浓度,收集24 h尿液检测尿蛋白肌酐比值及尿蛋白定量,Western blot法检测肾组织E-钙黏素(E-cadherin)、α-平滑肌肌动蛋白(α-SMA)及JAK/STAT通路信号蛋白酪氨酸激酶2(JAK2)、磷酸化蛋白酪氨酸激酶2 (p-JAK2)、信号转导与转录活化因子1(STAT1)、p-STAT1蛋白的表达水平.结果 IL-33组小鼠的BUN、尿蛋白肌酐比值及尿蛋白水平均高于模型组,差异均有统计学意义(均P<0.05);IL-33组小鼠肾小管上皮细胞α-SMA表达高于模型组,其差异有统计学意义(P<0.05);与模型组比较,IL-33组小鼠肾小管上皮细胞E-cadherin表达减少,p-JAK2、p-STAT1蛋白表达增加,差异均有统计学意义(均P<0.05);与模型组比较,IL-33组JAK2、STAT1蛋白水平无明显变化,差异均无统计学意义(均P>0.05).结论 IL-33可导致狼疮鼠肾小管间质病变,其机制可能与刺激JAK/STAT通路活化有关.

Objective To investigate the effects and mechanism of interleukin 33 (IL-33) on renal tubular injury in mice with lupus nephritis.Methods Twelve-week-old female MRL/lpr mice were randomly divided into model group,IL-33 group and solvent control group with 10 rats in each group.Ten female MRL/MP mice of the same age were used as normal control group.The mice in IL-33 group were intraperitoneally injected with 100 μL of phosphate buffer saline (PBS),containing 2 μg of recombinant mouse IL-33,once a day for 14 days.The mice in control group and the model group were intraperitoneally injected with the same dose of PBS.All the mice were sacrificed at 14 weeks of age.Serum creatinine (Cr) and urea nitrogen (BUN) concentrations were determined by serum separation.The urine in 24 hours was collected testing urinary protein creatinine ratio and urinary protein quantification.The contents of E-cadherin,α-SMA,and JAK/STAT pathway signaling proteins,including JAK2,p-JAK2,STAT1,and p-STAT1,were detected by Western blot.Results The BUN,urinary protein creatinine ratio and urine protein level of the IL-33 group were significantly higher than those of the model group (all P<0.05).The expression of renal tubular epithelial cells o-SMA in the IL-33 group was higher than that in the model group,and the difference was statistically significant (P<0.05).Compared with the model group,the expression of E-cadherin in the tubular epithelial cells of IL-33 group decreased and the expression of p-JAK2 and p-STAT1 protein increased,and the differences were all statistically significant (all P<0.05).Compared with the model group,the levels of JAK2 and STAT1 in IL-33 group change little,and the differences were not statistically significant (all P>0.05).Conclusions IL-33 can cause tubulointerstitial lesions in lupus mice,and its mechanism may be related to the activation of JAK/STAT pathway.