title: Rapamycin treatment dose-dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell-cycle-associated CDK1/cyclin axis.
abstract: 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/f3mice 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/f3mice 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/f3mice 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.
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.|State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Song
authors.initials: S
authors.lastname: Fan
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Jialin
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Mao
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Xiansheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.|State Key Laboratory of Molecular Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Guanqing
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Urology, PKD Center, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Chaozhao
authors.initials: C
authors.lastname: Liang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D018703:Founder Effect; D005786:Gene Expression Regulation; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D016203:CDC2 Protein Kinase; D016213:Cyclins; D019426:Integrases; D008840:Microfilament Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; C026615:villin; C546843:mTOR protein, mouse; C045073:Cre recombinase
keywords: ADPKD; Pkd2 mouse model; mTOR pathway; rapamycin