title: Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling.
abstract: 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. 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.
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hakim
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dyson
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Feeney
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davies
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Absorn
authors.initials: A
authors.lastname: Sriratana
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Monica N
authors.initials: MN
authors.lastname: Koenig
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Plotnikova
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia Development and Stem Cell program, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Smyth
authors.affiliation: Development and Stem Cell program, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Ricardo
authors.affiliation: Development and Stem Cell program, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.affiliation: Cancer Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia christina.mitchell@monash.edu.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D000072661:Ciliopathies / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D053492:Elafin / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018095:Germ-Line Mutation; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics*; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D053492:Elafin; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010744:Phosphoric Monoester Hydrolases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000099182:Phosphoinositide 5-Phosphatases; C506806:PI3 protein, human