High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis

Soumya Maity, Falguni Das, Nandini Ghosh-choudhury, Balakuntalam S Kasinath, Goutam Ghosh-choudhury

Research output: Contribution to journal › Letter

Abstract

The mechanism of PTEN repression by high glucose in diabetic nephropathy is not known. Using proximal tubular cells, we show that inhibition of PI3 kinase/Akt and their inactive enzymes prevents high glucose-induced PTEN downregulation. Similarly, rapamycin (Rapa) and shRaptor block suppression of PTEN by high glucose. In contrast, the constitutive activation of Akt and mechanistic target of rapamycin (mTOR)C1 decrease the expression of PTEN, similarly to high glucose. Remarkably, PI3 kinase/Akt/mTORC1 inhibition significantly attenuates high glucose-stimulated increase in miR-214, which targets PTEN, while constitutively active Akt/mTORC1 increases miR-214. Furthermore, anti-miR-214 and mTORC1 inhibition block high glucose-induced hypertrophy and fibronectin expression. These results reveal the first evidence for the presence of a high glucose-forced positive feedback conduit between the three-layered kinase cascade and miR-214/ PTEN in tubular cell injury.

Original languageEnglish (US)
JournalFEBS Letters
DOIs
StatePublished - Jan 1 2019

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Feedback
Glucose
Sirolimus
Phosphatidylinositol 3-Kinases
Diabetic Nephropathies
mechanistic target of rapamycin complex 1
Fibronectins
Hypertrophy
Phosphotransferases
Down-Regulation
Chemical activation
Wounds and Injuries
Enzymes

Keywords

  • diabetic nephropathy
  • fibrosis
  • microRNA
  • renal cell hypertrophy
  • signal transduction

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis. / Maity, Soumya; Das, Falguni; Ghosh-choudhury, Nandini; Kasinath, Balakuntalam S; Ghosh-choudhury, Goutam.

In: FEBS Letters, 01.01.2019.

Research output: Contribution to journal › Letter

Maity, S, Das, F, Ghosh-choudhury, N, Kasinath, BS & Ghosh-choudhury, G 2019, 'High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis', FEBS Letters. https://doi.org/10.1002/1873-3468.13505
Maity S, Das F, Ghosh-choudhury N, Kasinath BS, Ghosh-choudhury G. High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis. FEBS Letters. 2019 Jan 1. https://doi.org/10.1002/1873-3468.13505
Maity, Soumya ; Das, Falguni ; Ghosh-choudhury, Nandini ; Kasinath, Balakuntalam S ; Ghosh-choudhury, Goutam. / High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis. In: FEBS Letters. 2019.
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abstract = "The mechanism of PTEN repression by high glucose in diabetic nephropathy is not known. Using proximal tubular cells, we show that inhibition of PI3 kinase/Akt and their inactive enzymes prevents high glucose-induced PTEN downregulation. Similarly, rapamycin (Rapa) and shRaptor block suppression of PTEN by high glucose. In contrast, the constitutive activation of Akt and mechanistic target of rapamycin (mTOR)C1 decrease the expression of PTEN, similarly to high glucose. Remarkably, PI3 kinase/Akt/mTORC1 inhibition significantly attenuates high glucose-stimulated increase in miR-214, which targets PTEN, while constitutively active Akt/mTORC1 increases miR-214. Furthermore, anti-miR-214 and mTORC1 inhibition block high glucose-induced hypertrophy and fibronectin expression. These results reveal the first evidence for the presence of a high glucose-forced positive feedback conduit between the three-layered kinase cascade and miR-214/ PTEN in tubular cell injury.",
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AU - Maity, Soumya

AU - Das, Falguni

AU - Ghosh-choudhury, Nandini

AU - Kasinath, Balakuntalam S

AU - Ghosh-choudhury, Goutam

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The mechanism of PTEN repression by high glucose in diabetic nephropathy is not known. Using proximal tubular cells, we show that inhibition of PI3 kinase/Akt and their inactive enzymes prevents high glucose-induced PTEN downregulation. Similarly, rapamycin (Rapa) and shRaptor block suppression of PTEN by high glucose. In contrast, the constitutive activation of Akt and mechanistic target of rapamycin (mTOR)C1 decrease the expression of PTEN, similarly to high glucose. Remarkably, PI3 kinase/Akt/mTORC1 inhibition significantly attenuates high glucose-stimulated increase in miR-214, which targets PTEN, while constitutively active Akt/mTORC1 increases miR-214. Furthermore, anti-miR-214 and mTORC1 inhibition block high glucose-induced hypertrophy and fibronectin expression. These results reveal the first evidence for the presence of a high glucose-forced positive feedback conduit between the three-layered kinase cascade and miR-214/ PTEN in tubular cell injury.

AB - The mechanism of PTEN repression by high glucose in diabetic nephropathy is not known. Using proximal tubular cells, we show that inhibition of PI3 kinase/Akt and their inactive enzymes prevents high glucose-induced PTEN downregulation. Similarly, rapamycin (Rapa) and shRaptor block suppression of PTEN by high glucose. In contrast, the constitutive activation of Akt and mechanistic target of rapamycin (mTOR)C1 decrease the expression of PTEN, similarly to high glucose. Remarkably, PI3 kinase/Akt/mTORC1 inhibition significantly attenuates high glucose-stimulated increase in miR-214, which targets PTEN, while constitutively active Akt/mTORC1 increases miR-214. Furthermore, anti-miR-214 and mTORC1 inhibition block high glucose-induced hypertrophy and fibronectin expression. These results reveal the first evidence for the presence of a high glucose-forced positive feedback conduit between the three-layered kinase cascade and miR-214/ PTEN in tubular cell injury.

KW - diabetic nephropathy

KW - fibrosis

KW - microRNA

KW - renal cell hypertrophy

KW - signal transduction

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