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, 5584. (doi: 10.1038/s41598-018-22938-x) (PMID:29615724) (PMCID:PMC5882886)

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 > School of Cardiovascular & Metabolic Health
• Journal Name: Scientific Reports
• Publisher: Nature Research
• 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