Rapamycin treatment dose-dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell-cycle-associated CDK1/cyclin axis.
Rapamycin treatment dose-dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell-cycle-associated CDK1/cyclin axis.
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雷帕霉素治疗通过 mTORC1 和细胞周期相关 CDK1/细胞周期蛋白轴以剂量依赖性方式改善新型 ADPKD 小鼠模型中的囊性肾
DOI：
10.1111/jcmm.13091
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发表时间：
2017-08
影响因子：
5.3
通讯作者：
Liang C
中科院分区：
文献类型：
--
作者：
Li A;Fan S;Xu Y;Meng J;Shen X;Mao J;Zhang L;Zhang X;Moeckel G;Wu D;Wu G;Liang C
虽然对常染色体显性遗传性多囊肾病（ADPKD）及其发病机制的转化研究取得了相当大的进展，但目前缺乏标准化的动物模型用于临床前试验。在这项研究中，我们通过将Pkd 2条件性敲除小鼠（Pkd 2 f3）与Cre转基因小鼠交叉交配，建立了人ADPKD的正常小鼠模型，其中Cre由一系列肾脏相关启动子驱动。通过系统地表征小鼠模型，我们发现具有由小鼠绒毛蛋白-1启动子（Vil‐Cre; Pkd 2 f3/f3）驱动的Cre转基因的Pkd 2 f3/f3小鼠在肾脏、肝脏和胰腺中产生明显的囊肿，并在4-6个月大时死于终末期肾病（ESRD）。为了确定这些Vil-Cre; Pkd 2 f3/f3小鼠是否适合临床前试验，我们用高剂量的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂雷帕霉素治疗小鼠。高剂量雷帕霉素以时间和剂量依赖性方式显著延长Vil-Cre; Pkd 2 f3/f3小鼠的寿命，降低囊性指数和肾/体重比，并改善肾功能。此外，我们进一步发现，雷帕霉素通过下调细胞周期相关的细胞周期蛋白依赖性激酶1（CDK 1）和细胞周期蛋白（即细胞周期蛋白A、细胞周期蛋白B、细胞周期蛋白D1和细胞周期蛋白E）来阻止ADPKD肾脏中异常的上皮细胞增殖，这表明mTOR信号变化与囊肿形成中的多囊蛋白2功能障碍之间存在直接联系。我们新开发的ADPKD模型为将体内临床前结果转化为ADPKD治疗提供了一个实用的平台。雷帕霉素通过抑制异常升高的CDK 1和细胞周期蛋白抑制增殖的新定义的分子机制为ADPKD治疗的新分子靶点提供了线索。
Although translational research into autosomal dominant polycystic kidney disease (ADPKD) and its pathogenesis has made considerable progress, there is presently lack of standardized animal model for preclinical trials. In this study, we developed an orthologous mouse model of human ADPKD by cross‐mating Pkd2 conditional‐knockout mice (Pkd2 f3) to Cre transgenic mice in which Cre is driven by a spectrum of kidney‐related promoters. By systematically characterizing the mouse model, we found that Pkd2 f3/f3 mice with a Cre transgene driven by the mouse villin‐1 promoter (Vil‐Cre;Pkd2 f3/f3) develop overt cysts in the kidney, liver and pancreas and die of end‐stage renal disease (ESRD) at 4–6 months of age. To determine whether these Vil‐Cre;Pkd2 f3/f3 mice were suitable for preclinical trials, we treated the mice with the high‐dose mammalian target of rapamycin (mTOR) inhibitor rapamycin. High‐dose rapamycin significantly increased the lifespan, lowered the cystic index and kidney/body weight ratio and improved renal function in Vil‐Cre;Pkd2 f3/f3 mice in a time‐ and dose‐dependent manner. In addition, we further found that rapamycin arrested aberrant epithelial‐cell proliferation in the ADPKD kidney by down‐regulating the cell‐cycle‐associated cyclin‐dependent kinase 1 (CDK1) and cyclins, namely cyclin A, cyclin B, cyclin D1 and cyclin E, demonstrating a direct link between mTOR signalling changes and the polycystin‐2 dysfunction in cystogenesis. Our newly developed ADPKD model provides a practical platform for translating in vivo preclinical results into ADPKD therapies. The newly defined molecular mechanism by which rapamycin suppresses proliferation via inhibiting abnormally elevated CDK1 and cyclins offers clues to new molecular targets for ADPKD treatment.
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影响因子：
2.9
作者：
Gallagher AR;Germino GG;Somlo S
通讯作者：
Somlo S
影响因子：
3.5
作者：
Hartman, Tiffiney R.;Liu, Dongyan;Zilfou, Jack T.;Robb, Victoria;Morrison, Tasha;Watnick, Terry;Henske, Elizabeth P.
通讯作者：
Henske, Elizabeth P.
影响因子：
13.2
作者：
Ishikawa, I;Maeda, K;Kawaguchi, Y
通讯作者：
Kawaguchi, Y
影响因子：
--
作者：
Grech G;von Lindern M
通讯作者：
von Lindern M
DOI：
10.2215/cjn.02650313
发表时间：
2014-05-07
影响因子：
9.8
作者：
Braun, William E.;Schold, Jesse D.;Herts, Brian R.
通讯作者：
Herts, Brian R.