microRNA-181a Downregulates Deptor for TGFβ-induced Glomerular Mesangial Cell Hypertrophy and Matrix Protein Expression

Soumya Maity, Amit Bera, Nandini Ghosh-Choudhury, Falguni Das, Balakuntalam S. Kasinath, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

TGFβ contributes to mesangial cell hypertrophy and matrix protein increase in various kidney diseases including diabetic nephropathy. Deptor is an mTOR-interacting protein and suppresses mTORC1 and mTORC2 activities. We have recently shown that TGFβ-induced inhibition of deptor increases the mTOR activity. The mechanism by which TGFβ regulates deptor expression is not known. Here we identify deptor as a target of the microRNA-181a. We show that in mesangial cells, TGFβ increases the expression of miR-181a to downregulate deptor. Decrease in deptor augments mTORC2 activity, resulting in phosphorylation/activation of Akt kinase. Akt promotes inactivating phosphorylation of PRAS40 and tuberin, leading to stimulation of mTORC1. miR-181a-mimic increased mTORC1 and C2 activities, while anti-miR-181a inhibited them. mTORC1 controls protein synthesis via phosphorylation of translation initiation and elongation suppressors 4EBP-1 and eEF2 kinase. TGFβ-stimulated miR-181a increased the phosphorylation of 4EBP-1 and eEF2 kinase, resulting in their inactivation. miR-181a-dependent inactivation of eEF2 kinase caused dephosphorylation of eEF2. Consequently, miR-181a-mimic increased protein synthesis and hypertrophy of mesangial cells similar to TGFβ. Anti-miR-181a blocked these events in a deptor-dependent manner. Finally, TGFβ-miR-181a-driven deptor downregulation increased the expression of fibronectin. Our results identify a novel mechanism involving miR-181a-driven deptor downregulation, which contributes to mesangial cell pathologies in renal complications.

Original languageEnglish (US)
Pages (from-to)5-15
Number of pages11
JournalExperimental Cell Research
Volume364
Issue number1
DOIs
StatePublished - Mar 1 2018

Keywords

  • Deptor
  • Glomerulosclerosis
  • mTORC1
  • miR-181a

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'microRNA-181a Downregulates Deptor for TGFβ-induced Glomerular Mesangial Cell Hypertrophy and Matrix Protein Expression'. Together they form a unique fingerprint.

Cite this