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.
journal_name
Exp Cell Resjournal_title
Experimental cell researchauthors
Maity S,Bera A,Ghosh-Choudhury N,Das F,Kasinath BS,Choudhury GGdoi
10.1016/j.yexcr.2018.01.021subject
Has Abstractpub_date
2018-03-01 00:00:00pages
5-15issue
1eissn
0014-4827issn
1090-2422pii
S0014-4827(18)30032-6journal_volume
364pub_type
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journal_title:Experimental cell research
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