BAFF通过活化Toll样受体4参与IgA肾病的发病机制

BAFF is involved in the pathogenesis of IgA nephropathy by activating Toll-like receptor 4

目的探讨B细胞活化因子(BAFF)在免疫球蛋白A肾病(IgAN)中的作用及影响机制。方法利用野生型BAFF+/+小鼠和BAFF基因敲除(BAFF-/-)小鼠构建牛血清蛋白(BSA)、脂多糖(lipopolysaccharides,LPS)及四氯化碳联合应用诱导的IgA肾病模型。小鼠随机分为4组:野生对照组(BAFF+/+CON)、野生IgA肾病模型组(BAFF+/+IgAN)、BAFF基因敲除对照组(BAFF-/-CON)和BAFF基因敲除IgA肾病模型组(BAFF-/-IgAN)。用自动生化分析仪检测各组小鼠24h尿蛋白(24-UP)含量以及血浆中肌酐(Cr)、丙氨酸氨基转移酶(ALT)的含量;利用苏木精和曙红染色检测各组小鼠肾组织病理变化;蛋白免疫印迹法检测各组小鼠肾皮质组织中Toll样受体4(Toll-like receptor 4,TLR4)和转化生长因子β1(Transforming Growth Factor-β1,TGF-β1)蛋白水平;实时荧光定量PCR检测各组小鼠肾皮质组织中TLR4和TGF-β1的mRNA的表达。结果与对照组相比,BAFF+/+IgAN组24-UP、Cr和ALT的含量明显增加,肾脏病理损伤明显,且TLR4和TGF-β1的mRNA和蛋白表达显著升高,差异均有统计学意义(P<0.05);与BAFF+/+IgAN组相比,BAFF-/-IgAN组24-UP、Cr和ALT的含量明显减少,肾脏病理损伤轻微,而TLR4和TGF-β1的mRNA和蛋白表达显著下调,且差异有统计学意义(P<0.05)。结论抑制BAFF-TLR4信号通路可以改善IgA肾病症状。

Objective To investigate the effect of B cell-activating factor(BAFF)on immunoglobulin A nephropathy(IgAN)and its mechanism.Methods A wild-type BAFF+/+and BAFF gene knockout(BAFF-/-)mice were used to construct a model of IgA nephropathy induced by a combination of Albumin from serum(BSA),lipopolysaccharides(LPS)and carbon tetrlloride.Mice were randomly divided into 4 groups:wild control group(BAFF+/+CON),wild IgA nephropathy model group(BAFF+/+IgAN),BAFF knockout control group(BAFF-/-CON)and BAFF knockout IgA nephropathy model group(BAFF-/-IgAN).The contents of 24 h urinary protein(24-UP)as well as Creatinine(Cr)and Alanine aminotransferase(ALT)in plasma in each group were detected by an automatic biochemical analyzer.Hematoxylin and eosin staining were used to detect the pathological changes of renal tissues in each group.Theprotein levelof toll-like receptor 4(TLR4)and transforming growth factor-β1(TGF-β1)in the renal cortical tissues of each group was detected by western blotting.ThemRNA expression of TLR4 and TGF-β1 in renal cortical tissues of each group was detected by real-time fluorescence quantitative PCR.Results Compared with the control group,the expressions of 24-UP、Cr and ALT in the BAFF+/+IgAN group were significantly increased,and therenal pathological damage was obvious,while the mRNA and protein expressions of TLR4 and TGF-β1 were significantly upregulated,with statistically significant differences(P<0.05).Compared with the BAFF+/+IgAN group,the expression of 24-UP、Cr and ALT were significantly decreased in the BAFF-/-IgANgroup,while the mRNA and protein expressions of TLR4 and TGF-β1 were significantly down-regulated,with statistically significant differences(P<0.05).Conclusion BAFF-TLR4 signaling pathway plays an important role in IgA nephropathy.