Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease

Liu, Y. et al. (2018) Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease. Scientific Reports, 8(1), 5584. (doi: 10.1038/s41598-018-22938-x) (PMID:29615724) (PMCID:PMC5882886)

[img]
Preview
Text
160721.pdf - Published Version
Available under License Creative Commons Attribution.

3MB

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mischak, Professor Harald and Mullen, Dr Bill
Authors: Liu, Y., Pejchinovski, M., Wang, X., Fu, X., Castelletti, D., Watnick, T. J., Arcaro, A., Siwy, J., Mullen, W., Mischak, H., and Serra, A. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Scientific Reports 8(1):5584
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record