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High glucose increases miR‐214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis
Author(s) -
Maity Soumya,
Das Falguni,
GhoshChoudhury Nandini,
Kasinath Balakuntalam S.,
Ghosh Choudhury Goutam
Publication year - 2019
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13505
Subject(s) - pten , mtorc1 , protein kinase b , pi3k/akt/mtor pathway , chemistry , cancer research , downregulation and upregulation , microbiology and biotechnology , phosphorylation , signal transduction , biology , biochemistry , gene
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.