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 (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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common of a group of inherited kidney disorders characterized by progressive cyst development and various extrarenal manifestations [1, 2]
To validate Vil-Cre;Pkd2f3/f3 mice as a useful ADPKD model for preclinical trials, we used a rapamycin-based treatment that is known to be effective for ADPKD mice [40,41,42]
The response of the Vil-Cre; Pkd2f3/f3 mice to rapamycin was consistent with that reported for other ADPKD models, and the progression and timeline of the cystic phenotype and of renal failure in the Vil-Cre;Pkd2f3/f3 mice, along with the ease of evaluating the progression of the disease, make these mice a suitable model for evaluating and conducting preclinical trials of therapeutic interventions for ADPKD
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common of a group of inherited kidney disorders characterized by progressive cyst development and various extrarenal manifestations [1, 2]. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine We developed and well characterized a newly established ADPKD model and demonstrated that rapamycin inhibits cystic progression in the ADPKD kidney by down-regulating the cell-cycle-associated CDK1 and cyclins (cyclin A, cyclin B, cyclin D1 and cyclin E), thereby arresting aberrant proliferation of the renal epithelia. Statistics and detailed procedures of cystic index calculation, proliferation and apoptosis are described in Supplementary Methods D in Appendix S1
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