TY - JOUR
T1 - High glucose increases miR-214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis
AU - Maity, Soumya
AU - Das, Falguni
AU - Ghosh-choudhury, Nandini
AU - Kasinath, Balakuntalam S
AU - Ghosh Choudhury, Goutam
N1 - Funding Information:
This work was supported by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service Merit Review Award 2I01 BX000926 to GGC. GGC is a recipient of Research Career Scientist Award IK6BX00361 from the Department of Veterans Affairs Biomedical Laboratory Research and Development Service.
Publisher Copyright:
Published 2019. This article is a U.S. Government work and is in the public domain in the USA
PY - 2019/8
Y1 - 2019/8
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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U2 - 10.1002/1873-3468.13505
DO - 10.1002/1873-3468.13505
M3 - Article
C2 - 31240704
AN - SCOPUS:85068503840
VL - 593
SP - 2261
EP - 2272
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 16
ER -