固本通络方基于肠肾关联治疗小鼠IgA肾病的实验研究

Experimental study on effects of Guben Tongluo Formula in IgA nephropathy mice based on intestine-kidney connection

目的探讨固本通络方对IgA肾病(IgA nephropathy,IgAN)的疗效及作用机制。方法建立α1K1-CD89 Tg转基因IgAN小鼠模型,随机分为假手术组、模型组、骨化三醇组、固本通络方组、MYD88过表达+固本通络方组。各组分别进行相应干预。观察小鼠外周血IgA及异常糖基化IgA1水平,肠黏膜髓样分化因子88(MYD88)、核因子κB(NF-κB)、B细胞活化因子(B-cell activating factor,BAFF)和增殖诱导配体(a proliferation-inducing ligand,APRIL)、β1,3-半乳糖转移酶(β1,3-galac-tosyltransferase,C1GalT1)及伴侣蛋白Cosmc的表达,肾脏损伤情况(尿蛋白定量、尿红细胞、血肌酐)。结果与假手术组比较,模型组小鼠外周血IgA、异常糖基化IgA1水平、血肌酐,肠黏膜MYD88、NF-κB、BAFF、APRIL表达,尿蛋白定量和尿红细胞均显著上升,C1GalT1及Cosmc的表达显著降低;骨化三醇和固本通络方治疗后可显著改善以上异常,且固本通络方组效果略优于骨化三醇组;MYD88过表达后固本通络方的治疗效果受到明显抑制。结论固本通络方可能通过抑制肠道MYD88/NF-KB通路,调控B细胞的激活,进而减少异常糖基化IgA1产生以治疗IgAN。

Objective To investigate the therapeutic effect and mechanisms of Guben Tongluo Formula on IgA nephropathy( IgAN). Methods The IgAN model was established in α1k1-CD89 Tg transgenic mice. The model mice were randomly divided into the sham operation group,model group,calcitriol group,Guben Tongluo Formula group and MYD88 overexpression plus Guben Tongluo Formula group. Each group was treated with the corresponding intervention. The levels of IgA and abnormal glycosylation IgA1 in peripheral blood were observed. The expression levels of myeloid differentiation factor 88( MYD88),nuclear factor-κB( NF-κB),B-cell activating factor( BAFF) and a proliferation-inducing ligand( APRIL),β1,3-galac-tosyltransferase( C1GalT1) and chaperonin Cosmc in intestinal mucosa were detected. The kidney damages( proteinuria,urinary erythrocytes and serum creatinine) were observed. Results Compared with the sham operation group,the levels of IgA and abnormal glycosylation IgA1 in peripheral blood,serum creatinine,the expression levels of MYD88,NF-κB,BAFF,APRIL in intestinal mucosa,the levels of urine protein and urinary erythrocytes were significantly increased in the model group,whereas the expressions of C1GalT1 and Cosmc were significantly down-regulated. Both calcitriol and Guben Tongluo Formula could significantly ameliorate the mentioned abnormalities,and the effects in Guben Tongluo Formula group were slightly better than those in calcitriol group. However,the therapeutic effects of Guben Tongluo Formula were significantly inhibited when MYD88 was over expressed. Conclusion Guben Tongluo Formula can inhibit MYD88/NF-κB pathway,regulate the activation of B lymphocyte,and thereby reduce the production of abnormal glycosylation IgA1,which may be the mechanisms of Guben Tongluo Formula in the treatment of IgAN.