The Influence And Significance Of Tacrolimus On The Expression Of MDR1 And Glycoprotein P-gp170 In Children With Steroid-resistant Nephrotic Syndrome

Objective To compare the expression of MDR1 m RNA and its glycoprotein P-gp170 from children with idiopathic nephrotic syndrome(INS) in different periods of the therapy.To investigate the influence and significance of tacrolimus(TAC),a new type of calcineurin inhibitor(CNI) on the expression of MDR1 and P-gp170 from children with steroid-resistant nephrotic syndrome(SRNS).Methods 36 children with INS admitted were divided into two groups of 20 SSNS and16SRNS according to prednisone treatment.And 20 healthy children serving as control.RT-PCR and FCM were applied to detect the expression of MDR1 m RNA and P-gp170 on PBMC at different time(1、before prednisone treatment; 2、after 4 weeks of prednisone treatment;3 、4 weeks after prednisone decrement in SSNS or 4 weeks after TAC treatment in SRNS;4、8 weeks after TAC treatment in SRNS).The expression of renal P-gp170 derived from 16 SRNS and 10 controls were observed via IHC.Results 1)A highly positive correlation was found between MDR1 m RNA and P-gp170 expression levels on PBMC of INS(r=0.854,P<0.01). 2)Before prednisone treatment,the expression levels of MDR1 m RNA and the P-gp170 on PBMC of children with INS were obviously higher than that in control(P<0.05). 3)After 4 weeks of prednisone treatment,the expression levels of MDR1 m RNA and the P-gp170 in children with SSNS and SRNS were higher than before(P<0.01). 4)Four weeks after prednisone decrement,the expression levels of MDR1 m RNA and the P-gp170 in children with SSNS were obviously sliding,of which the difference is significantly(P<0.01),while comparing with before prednisone treatment,no significant difference was found in the expression levels of MDR1 m RNA and the P-gp170(P>0.05). 5)Four or eight weeks after TAC treatment,the expression levels of MDR1 m RNA and the P-gp170 in children with SRNSwere obviously sliding,of which the differnece is significantly(P<0.01),even though the expression levels of the gene and its protein in children with SRNS after 4 weeks TAC treatment were higher than that in SSNS after 4 weeks prednisone decrement(P<0.01).6)In SRNS,average values of MDR1 m RNA and P-gp170 expression after eight weeks TAC treatment were lower than that after four weeks TAC treatment(P<0.01),while no significant difference was found in MDR1 m RNA and P-gp170 expression levels between8 weeks after TAC treatment and before prednisone treatment. 7)The expression of renal P-gp170 in SRNS and control were distributed in renal tubule and renal interstitium;While the expression of renal P-gp170 in proximal convoluted tubules and distal convoluted tubules of SRNS group were both higher than that in control(P<0.01),in SRNS group,the expression of renal P-gp170 in proximal convoluted tubules were higher than that in distal convoluted tubules(P<0.01). 8)After 4 weeks of prednisone treatment,there was a positive correlation between Lymphocytes P-gp170 and renal P-gp170 expression in proximal convoluted tubules and distal convoluted tubules of SRNS group(r=0.547,P<0.05;r=0.541,P<0.05). 9)Before prednisone treatment,there was also a positive correlation between PBMC P-gp170 and 24 h urine portein in SRNS group(r=0.712,P<0.01).Conclusion 1.A positive correlation was found between MDR1 m RNA and the P-gp170 expression level on membrane of peripheral blood mononuclear cells. Further to say, the more expressions of MDR1 m RNA, the more the average values of the P-gp170 expression level on membrane of peripheral blood mononuclear cells. 2.Up-regulating the expression of P-gp170 in children with SRNS may participate in the course of occurrence and development of steroid resistance. 3.Mechanism of steroid resistance in SRNS may attribute to up-regulating the expression of renal P-gp170 primarily. 4.Tacrolimus make a contribution to up-regulating the expression of MDR1 m RNA and P-gp170 on membrane of peripheral blood mononuclear cells to some extent which may reverse steroid resistance in children with nephrotic syndrome.