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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DOI：
10.1111/jcmm.13091
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Chaozhao Liang
中科院分区：
文献类型：
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作者：
Ao Li;Song Fan;Yuchen Xu;Jialin Meng;Xufeng Shen;Jun Mao;Li Zhang;Xiansheng Zhang;Gilbert Moeckel;Dianqing Wu;Guanqing Wu;Chaozhao Liang
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 (Pkd2f3) 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 Pkd2f3/f3 mice with a Cre transgene driven by the.mouse villin-1 promoter (Vil-Cre;Pkd2f3/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;Pkd2f3/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;Pkd2f3/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.
