Rapamycin treatment dose-dependently improves the cystic kidney in a new ADPKD mouse modelviathe mTORC1 and cell-cycle-associated CDK1/cyclin axis

Autor: Song Fan, Gilbert W. Moeckel, Jun Mao, Yuchen Xu, Xufeng Shen, Dianqing Wu, Chaozhao Liang, Guanqing Wu, Xiansheng Zhang, Li Zhang, Ao Li, Jialin Meng
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Cyclin E
Cyclin A
Cyclin B
mTORC1
Kidney
urologic and male genital diseases
Mice
Promoter Regions
Genetic
Cystic kidney
Antibiotics
Antineoplastic
biology
TOR Serine-Threonine Kinases
Cell Cycle
Microfilament Proteins
Polycystic Kidney
Autosomal Dominant
female genital diseases and pregnancy complications
Founder Effect
mTOR pathway
Molecular Medicine
Female
Original Article
Signal Transduction
medicine.medical_specialty
TRPP Cation Channels
Autosomal dominant polycystic kidney disease
Mice
Transgenic
03 medical and health sciences
Cyclin D1
Cyclins
Internal medicine
CDC2 Protein Kinase
medicine
Animals
Humans
Pkd2 mouse model
ADPKD
Sirolimus
Cyclin-dependent kinase 1
Dose-Response Relationship
Drug
Integrases
rapamycin
urogenital system
business.industry
Original Articles
Cell Biology
medicine.disease
030104 developmental biology
Endocrinology
Gene Expression Regulation
biology.protein
Cancer research
business
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-1838
Popis: 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.
Databáze: OpenAIRE
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