Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling

Sandra Hakim, Jennifer M Dyson, Sandra J Feeney, Elizabeth M Davies, Absorn Sriratana, Monica N Koenig, Olga Plotnikova, Ian M Smyth, Sharon D Ricardo, Robin M Hobbs, Christina A Mitchell

Research output: Contribution to journalArticleResearchpeer-review

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. 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.
Original languageEnglish
Pages (from-to)2295-2313
Number of pages19
JournalHuman Molecular Genetics
Volume25
Issue number11
DOIs
Publication statusPublished - 2016

Cite this

Hakim, Sandra ; Dyson, Jennifer M ; Feeney, Sandra J ; Davies, Elizabeth M ; Sriratana, Absorn ; Koenig, Monica N ; Plotnikova, Olga ; Smyth, Ian M ; Ricardo, Sharon D ; Hobbs, Robin M ; Mitchell, Christina A. / Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 11. pp. 2295-2313.
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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. 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.",
author = "Sandra Hakim and Dyson, {Jennifer M} and Feeney, {Sandra J} and Davies, {Elizabeth M} and Absorn Sriratana and Koenig, {Monica N} and Olga Plotnikova and Smyth, {Ian M} and Ricardo, {Sharon D} and Hobbs, {Robin M} and Mitchell, {Christina A}",
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Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling. / Hakim, Sandra; Dyson, Jennifer M; Feeney, Sandra J; Davies, Elizabeth M; Sriratana, Absorn; Koenig, Monica N; Plotnikova, Olga; Smyth, Ian M; Ricardo, Sharon D; Hobbs, Robin M; Mitchell, Christina A.

In: Human Molecular Genetics, Vol. 25, No. 11, 2016, p. 2295-2313.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling

AU - Hakim, Sandra

AU - Dyson, Jennifer M

AU - Feeney, Sandra J

AU - Davies, Elizabeth M

AU - Sriratana, Absorn

AU - Koenig, Monica N

AU - Plotnikova, Olga

AU - Smyth, Ian M

AU - Ricardo, Sharon D

AU - Hobbs, Robin M

AU - Mitchell, Christina A

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N2 - 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.

AB - 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.

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