The Effect Of Montelukast Sodium On IgE-mediated Adriamycin-induced Nephropathy

[Objective] Some idiopathic nephrotic syndrome is heterogeneous and multiple.Recent clinical studies have found that some INS have common clinical features with atopic diseases in children: Such as it attacks in a special season,repeated episodes of children with glucocorticoid treatment.Dysfunction of Th1/Th2 cell,abnormal increase of Ig E and activation of leukotriene pathway play an important role in many kinds of atopic diseases.Hence we provided that INS have some similar pathogenesis with atopic disease,which may be an atopic disease with Th2 activation promoting the Ig E abnormal increase.Leukotriene pathway may be involved in the pathogenesis of INS.Our study established the adriamycin-induced nephropathy model,to detect the expression of Th1/Th2 cytokines,Ig E and Cys LT1 R.Then with leukotriene receptor antagonist montelukast Sodium treatment,to investigate whether INS and atopic diseases have similar pathogenesis and intervention effect of montelukast sodium.To provided the theoretical basis and experimental basis for the clinical application of montelukast sodium in the INS,eventually.[Methods] 48 healty male SD rats were divided randomly into 2 groups: 1.Normal control group(Sham group,n=24),2.Adriamycin-induced nephropathy group(ADR group,n=48).The adriamycin-induced nephropathy model was established by a single tail vein injection of doxorubicin hydrochloride,and each group was sacrificed 6 rats after injection of 2,4,6 and 8 weeks,respectively.Then the blood samples,24 hour urine and kidney tissues were obtained.(2)Group assignments were made via random drug intervention treatment: with the induction of adriamycin-induced nephropathy model sucessfully at the end of 4-week.24 rats of adriamycin-induced nephropathy model were divided randomly into 4 groups: 1.Prednisone group(ADR+P groups,n=6),2.Montelukast sodium group(ADR+M groups,n=6),3.Prednisone combined with Montelukast sodium group(ADR+P+M group,n=6),4.Normal saline group(ADR+N group,n=6).(3)Concentrations of 24 h UPro,ALB,TG,Cho L were assayed by autoanalyzer.The histological changes of kidney were observed by microscope after HE staining.The ultrastructural changes of kidney tissue were observed by transmission electron microscope(TEM).Concentrations of Ig E,IL-4,IL-5,IL-10,IL-13,IL-2,FN-? in the sera were measured by ELISA.Relative expression of Cys LT1 R m RNA and protein expression was detected by q RT-PCR and Western blot in inperipheral blood and kidney tissue.[Results](1)With the induction of adriamycin-induced nephropathy model sucessfully at the end of 4 week,we observed a significant upregulation in concentrations of 24 h UPro,TG,Cho L and a significant reduced of ALB in ADR group than that in Sham group.HE staining and TEM: The glomeruli become enlarged,extensive foot process effacement was seem in the glomerulus,and inflammatory cell infiltrating in tubulointerstitial areas.The pathological damage was increased with the time gone.(2)The expression level of Ig E IL-5,IL-10 and IL-13 showed an increasing with the passage of time in ADR group at each time point than that in Sham group(P < 0.05),along with the time increased,compared with the Sham group had significant difference(P < 0.05).But IL-4,IL-2 and IFN-? with those of the Sham group had no significant difference(P > 0.05).(3)concentrations of Cys LT1 R m RNA and protein expression were much higher in ADR group at each time point than that in Sham group(P < 0.05),then maintained at a high level.(4)Correlation analysis in ADR group: 24 h UPro is positive correlated to Ig E IL-5,IL-10,IL-13 and the m RNA relative expression of Cys LT1 R,but it is no relation to IL-4.The m RNA relative expression of Cys LT1 R is positive correlated to Ig E.(5)Adriamycin-induced nephropathy rats were treated with prednisone and moontelukast(ADR+P group,ADR+M group,ADR+P+M group)for 4 weeks:(1)we observed a significant reduced of 24 h UPro,TG and Cho L and a significant upregulation in concentrations of ALB in ADR+ P group,ADR+M group,ADR+P+M group than that ADR+N group,the ADR+P+M group was the most significant(P < 0.05).(2)Renal tissue lesion become mild in ADR+P group,ADR+M group,ADR+P+M group than that ADR+N group,the ADR+P+M group were attenuated dramatically.(3)A significant reduced of oncenctrations of Ig E and IL-13 expression in ADR+P group,ADR+M group,ADR+P+M group than that in ADR+N group,the ADR+P+M group was the most significant reduced(P < 0.001).(4)A significant reduced of Cys LT1 R m RNA and protein expression in ADR+P group,ADR+M group,ADR+P+M group than that in ADR+N group,the ADR+P+M group was the most significant reduced(P < 0.001).[Conclusion](1)Adriamycin-induced nephropathy is a kind of allergic disease mediated by abnormal elevation of Ig E.Th2 cell activation is one of the pathogenesis of adriamycin-induced nephropathy.(2)Leukotrienes signaling pathway activtion involve in the occurrence and development of adriamycin-induced nephropathy.(3)The intervention of montelukast combined with glucocorticosteroids can reduce the pathological changes of renal tissue in adriamycin-induced nephropathy,and effectively inhibit the recurrence.