Long-term rapamycin therapy in the Han:SPRD rat model of polycystic kidney disease (PKD).
Long-term rapamycin therapy in the Han:SPRD rat model of polycystic kidney disease (PKD).
复制标题
DOI：
10.1093/ndt/gfp129
复制
发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
I. Zafar;Franck A. Belibi;Zhibin He;C. Edelstein
中科院分区：
文献类型：
--
作者：
I. Zafar;Franck A. Belibi;Zhibin He;C. Edelstein
背景短期研究表明，雷帕霉素或依维莫司治疗可减少多囊肾病（PKD）动物模型中囊肿的形成并改善肾功能。常染色体显性多囊肾病 (ADPKD) 患者可能需要终身接受雷帕霉素治疗。方法 雄性汉族：PKD（Cy/+）SPRD 大鼠在 1 至 12 月龄期间接受雷帕霉素（0.2 mg/kg/天腹腔注射）或载体治疗。 8 周龄时雷帕霉素的平均谷水平 (ng/mL) 为 6.6 +/- 0.1。十二个月大的同窝仔猪（+/+）用作正常对照。结果 与正常同窝对照大鼠相比，用媒介物治疗的 12 个月大雄性 Cy/+ 大鼠的肾脏体积增加了一倍多，出现严重慢性肾功能衰竭、严重高血压和心脏重量增加 (+/+)。雷帕霉素治疗后，12月龄Cy/+大鼠的肾体积、肾功能、血压和心脏重量均显着改善，与对照组无统计学差异。雷帕霉素使囊肿体积密度 (CVD) 降低 72%。在 12 个月大的 Cy/+ 大鼠中，哺乳动物雷帕霉素靶点 (mTOR) 在心脏中被激活，这一点通过受雷帕霉素抑制的磷酸化 S6 蛋白显着增加得到证明。结论 总之，长期雷帕霉素治疗 Cy/+ 大鼠可导致肾体积、肾功能、血压和心脏重量正常化。据报道，雷帕霉素可降低 PKD 大鼠的高血压、心脏扩大和心脏 mTOR 信号传导。雷帕霉素治疗的唯一副作用是体重下降 11%。
BACKGROUND Short-term studies have demonstrated that rapamycin or everolimus treatment decreases cyst formation and improves renal function in animal models of polycystic kidney disease (PKD). Autosomal dominant polycystic kidney disease (ADPKD) patients would likely require life-long treatment with rapamycin. METHODS Male Han:SPRD rats with PKD (Cy/+) were treated with rapamycin (0.2 mg/kg/day IP) or vehicle from 1 to 12 months of age. Mean trough levels of rapamycin (ng/mL) were 6.6 +/- 0.1 at 8 weeks of age. Twelve-month-old littermates (+/+) were used as normal controls. RESULTS Twelve-month-old male Cy/+ rats treated with the vehicle had a more than doubling of kidney volume, severe chronic renal failure, severe hypertension and increased heart weight compared to normal littermate controls (+/+). After rapamycin treatment, 12-month-old Cy/+ rats had markedly improved kidney volume, renal function, blood pressure and heart weight not statistically different from controls. Rapamycin reduced the cyst volume density (CVD) by 72%. Mammalian target of rapamycin (mTOR) activation in the heart, as evidenced by a marked increase in the phospho-S6 protein that was inhibited by rapamycin, was demonstrated in 12-month-old Cy/+ rats. CONCLUSION In conclusion, long-term rapamycin treatment in Cy/+ rats results in a normalization of kidney volume, renal function, blood pressure and heart weight. The novel finding that rapamycin decreases hypertension, heart enlargement and mTOR signalling in the heart in PKD rats is reported. The only side effect of rapamycin treatment was an 11% decrease in body weight.