Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling
| Autor: | Jennifer M Dyson, Absorn Sriratana, Monica N. Koenig, Sharon D. Ricardo, Sandra Hakim, Robin M. Hobbs, Ian M. Smyth, Elizabeth M Davies, Sandra J Feeney, Christina Anne Mitchell, Olga V. Plotnikova |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
mTORC1 Mechanistic Target of Rapamycin Complex 1 Kidney Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Polycystic kidney disease Animals Humans Molecular Biology Protein kinase B Germ-Line Mutation Genetics (clinical) PI3K/AKT/mTOR pathway Sequence Deletion Sirolimus Polycystic Kidney Diseases Phosphoinositide 3-kinase biology TOR Serine-Threonine Kinases Cilium Epithelial Cells General Medicine medicine.disease Ciliopathies Phosphoric Monoester Hydrolases Elafin Cell biology Disease Models Animal Ciliopathy 030104 developmental biology medicine.anatomical_structure Multiprotein Complexes 030220 oncology & carcinogenesis biology.protein Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Human Molecular Genetics. 25:2295-2313 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddw097 |
| Popis: | 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)P3 and is mutated in ciliopathy syndromes. Germline Inpp5e deletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development upon Inpp5e loss remain unknown. Here, we show conditional inactivation of Inpp5e in 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 mammalian target of rapamycin complex 1 (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. |
| Databáze: | OpenAIRE |
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