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In this study, we developed an orthologous mouse model of human <jats:styled-content style=\"fixed-case\">ADPKD<\/jats:styled-content> by cross\u2010mating <jats:italic>Pkd2<\/jats:italic> conditional\u2010knockout mice (<jats:italic>Pkd2<\/jats:italic><jats:sup>f3<\/jats:sup>) to Cre transgenic mice in which Cre is driven by a spectrum of kidney\u2010related promoters. By systematically characterizing the mouse model, we found that <jats:italic>Pkd2<\/jats:italic><jats:sup>f3\/f3<\/jats:sup> mice with a Cre transgene driven by the mouse <jats:italic>villin\u2010<\/jats:italic>1 promoter (<jats:italic>Vil<\/jats:italic>\u2010Cre;<jats:italic>Pkd2<\/jats:italic><jats:sup>f3\/f3<\/jats:sup>) develop overt cysts in the kidney, liver and pancreas and die of end\u2010stage renal disease (<jats:styled-content style=\"fixed-case\">ESRD<\/jats:styled-content>) at 4\u20136 months of age. To determine whether these <jats:italic>Vil<\/jats:italic>\u2010Cre;<jats:italic>Pkd2<\/jats:italic><jats:sup>f3\/f3<\/jats:sup> mice were suitable for preclinical trials, we treated the mice with the high\u2010dose mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) inhibitor rapamycin. High\u2010dose rapamycin significantly increased the lifespan, lowered the cystic index and kidney\/body weight ratio and improved renal function in <jats:italic>Vil<\/jats:italic>\u2010Cre;<jats:italic>Pkd2<\/jats:italic><jats:sup>f3\/f3<\/jats:sup> mice in a time\u2010 and dose\u2010dependent manner. In addition, we further found that rapamycin arrested aberrant epithelial\u2010cell proliferation in the <jats:styled-content style=\"fixed-case\">ADPKD<\/jats:styled-content> kidney by down\u2010regulating the cell\u2010cycle\u2010associated cyclin\u2010dependent kinase 1 (<jats:styled-content style=\"fixed-case\">CDK<\/jats:styled-content>1) and cyclins, namely cyclin A, cyclin B, cyclin D1 and cyclin E, demonstrating a direct link between <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signalling changes and the polycystin\u20102 dysfunction in cystogenesis. Our newly developed <jats:styled-content style=\"fixed-case\">ADPKD<\/jats:styled-content> model provides a practical platform for translating <jats:italic>in vivo<\/jats:italic> preclinical results into <jats:styled-content style=\"fixed-case\">ADPKD<\/jats:styled-content> therapies. The newly defined molecular mechanism by which rapamycin suppresses proliferation <jats:italic>via<\/jats:italic> inhibiting abnormally elevated <jats:styled-content style=\"fixed-case\">CDK<\/jats:styled-content>1 and cyclins offers clues to new molecular targets for <jats:styled-content style=\"fixed-case\">ADPKD<\/jats:styled-content> treatment.<\/jats:p>","DOI":"10.1111\/jcmm.13091","type":"journal-article","created":{"date-parts":[[2017,2,28]],"date-time":"2017-02-28T11:52:12Z","timestamp":1488282732000},"page":"1619-1635","source":"Crossref","is-referenced-by-count":41,"title":["Rapamycin treatment dose\u2010dependently improves the cystic kidney in a new <scp>ADPKD<\/scp> mouse model <i>via<\/i> the <scp>mTORC<\/scp>1 and cell\u2010cycle\u2010associated <scp>CDK<\/scp>1\/cyclin axis"],"prefix":"10.1111","volume":"21","author":[{"given":"Ao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology PKD Center The First Affiliated Hospital of Anhui Medical 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