他克莫司与西罗莫司根据细胞周期序贯用药对阿霉素肾病大鼠的影响

The efficacy research of tacrolimu and sirolimus sequential therapy according to the cell cycle in the Adria- mycin-induced nephropathy rats

目的观察他克莫司、西罗莫司根据细胞周期序贯联合用药对阿霉素肾病大鼠的治疗效果。方法将24只雄性SD大鼠模型完全随即分为正常对照组、肾病组及治疗组，各8只；测定3组大鼠的尿蛋白定量、血生化指标；免疫组化、定时定量聚合酶链反应检测肾组织Nephrin、Podocin表达以及肾组织结缔组织生长因子（CTGF）的表达。结果①肾病组在12周末可见肾小球出现局灶节段性硬化，治疗组病理变化明显减轻。②肾病组4、8、12周末尿蛋白定量[分别为（276．41±11．12）、（355．76±14．10）、（338．92±15．87）rng]均明显高于对照组[分别为（12．184-1．38）、（12．98±2．07）、（13．56±2．70）mg，P〈0．01）]，治疗组大鼠尿蛋白定量在8、12周末[分别为（160．64±13．72）、（126．30±14．65）mg]均明显低于肾病组（P〈0．05），但高于对照组；肾病组TP、ALB明显低于对照组（P〈0．01），肾病组TG、胆固醇明显高于对照组（P〈0．01），治疗组TP、ALB明显高于肾病组（P〈0．05）。③在12周末肾病组大鼠Nephrin、Podocin蛋白和mRNA表达明显减少（P〈0．01），治疗组表达较肾病组上调（P〈0．05）。④在12周末肾病组CTGF蛋白表达较对照组明显增加（P〈0．01），治疗组较肾病组明显减少（P〈0．05）。结论他克莫司、西罗英司根据细胞周期序贯联合用药对阿霉素肾病大鼠肾组织病理学变化均有明显改善，可有效减少阿霉素肾病大鼠的尿蛋白；升高TP和ALB，降低TG和胆固醇；并可恢复足细胞相关蛋白的表达，改善肾脏纤维化。

Objective To assess the therapeutic effects of the sequential therapy regimens according to the theory of cell cycle in adriamycin-induced nepbropathy（AIN）rats. Methods AIN model rats were randomly divided into three groups ： control group （ n = 8） , AIN model group （ n = 8 ） and treated group （ n = 8 ）. The level of 24 hour urinary protein, serum total protein （ TP）, albumin （ ALB ）, cholesterin （ Chol）, triglyeride （ TG）, serum urea nitrogen （BUN）, serum ereatinine （Scr）were measured. The expression of Nephrin and Podocin were analyzed by immunohistoehemistry and Real-time PCR, connective tissue growth factor （CTGF） were detected by westernblot. Results （~）The sequential combined regimens can improve the pathological changes in Adriamycin-induced nephrop- athy rats. （2）The level of 24 h urinary protein in model group at 4 th, 8 th and 12 th week [ respectively （276.41 ±11.12） , （355.76 ± 14. 10） and （338.92 ± 15.87 ）mg] were obviously higher than control group [ respectively （ 12.18± 1.38） , （ 12.98 ±2.07） and （ 13.56±2.70） mg]. The level of 24 hour urinary protein in model group at 8th and 12 th week [ respectively （ 160.64 ~ 13.72 ） and （ 126.30 ~ 14.65 ） mg] was obviously lower than model group（ P 〈 0.05 ）. The levels of TP and ALB in treatment group were significantly higher in AIN model group, and the levels of TG and Chol were significantly lower in model group. （~ne results of immunohistochemistry indicated the expression of Nephrin and Podocin in treatment group were higher than those in model group（P 〈0. 05）. （~）The results of westernblot indicated the expression of CTGF in treatment group was higher than that in AIN model group （P 〈 0.05）. Conclusions The sequential combined regimens can improve the pathological changes in Adriamycin-in- duced nephropathy rats, decrease the excretion of urinary protein,increase the levels of TP and ALB and decrease the levels of TG and Chol. It also can increase the expression of Nephrin and Podocin, and ameliorate kidney fibrosis.