Polycystic kidney disease (PKD) is a common cause of renal failure with few effective treatments. INPP5E is an inositol polyphosphate 5-phosphatase that dephosphorylates phosphoinositide 3-kinase (PI3K)-generated PI(3,4,5)P3and is mutated in ciliopathy syndromes.
GermlineInpp5edeletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development uponInpp5eloss remain unknown. Here, we show conditional inactivation ofInpp5ein mouse kidney epithelium results in severe PKD and renal failure, associated with a partial reduction in cilia number and hyperactivation of PI3K/Akt and downstream mTORC1 signaling. Treatment with an mTORC1 inhibitor improved kidney morphology and function, but did not affect cilia number or length. Therefore, we identify Inpp5e as an essential inhibitor of the PI3K/Akt/mTORC1 signaling axis in renal epithelial cells, and demonstrate a critical role for Inpp5e-dependent mTORC1 regulation in PKD suppression.
Human molecular genetics. 2016 Apr 07 [Epub ahead of print]
Sandra Hakim, Jennifer M Dyson, Sandra J Feeney, Elizabeth M Davies, Absorn Sriratana, Monica N Koenig, Olga V Plotnikova, Ian M Smyth, Sharon D Ricardo, Robin M Hobbs, Christina A Mitchell
1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia 2. Development and Stem Cell program, Department of Anatomy and Developmental Biology, Monash University, Clayton Victoria 3800, Australia., 2. Development and Stem Cell program, Department of Anatomy and Developmental Biology, Monash University, Clayton Victoria 3800, Australia., 2. Development and Stem Cell program, Department of Anatomy and Developmental Biology, Monash University, Clayton Victoria 3800, Australia 3. Australian Regenerative Medicine Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton Victoria, 3800, Australia., 1. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton Victoria 3800, Australia