title: High glucose enhances microRNA-26a to activate mTORC1 for mesangial cell hypertrophy and matrix protein expression.
abstract: High glucose milieu inhibits PTEN expression to activate Akt kinase and induces glomerular mesangial cell hypertrophy and matrix protein expression in diabetic nephropathy. Specific mechanism by which high glucose inhibits PTEN expression is not clear. We found that high glucose increased the expression of the microRNA-26a (miR-26a) in mesangial cells. Using a sensor plasmid with 3'UTR-driven luciferase, we showed PTEN as a target of miR-26a in response to high glucose. Overexpression of miR-26a reduced the PTEN protein levels resulting in increased Akt kinase activity similar to high glucose treatment. In contrast, anti-miR-26a reversed high glucose-induced suppression of PTEN with concomitant inhibition of Akt kinase activity. Akt-mediated phosphorylation of tuberin and PRAS40 regulates mTORC1, which is necessary for mesangial cell hypertrophy and matrix protein expression. Inhibition of high glucose-induced miR-26a blocked phosphorylation of tuberin and PRAS40, which lead to suppression of phosphorylation of S6 kinase and 4EBP-1, two substrates of mTORC1. Furthermore, we show that expression of miR-26a induced mesangial cell hypertrophy and increased fibronectin and collagen I (α2) expression similar to that observed with the cells incubated with high glucose. Anti-miR-26a inhibited these phenomena in response to high glucose. Together our results provide the first evidence for the involvement of miR-26a in high glucose-induced mesangial cell hypertrophy and matrix protein expression. These data indicate the potential therapeutic utility of anti-miR-26a for the complications of diabetic kidney disease.
authors: Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States.
authors: Nirmalya
authors: N
authors: Dey
authors: Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States.
authors: Amit
authors: A
authors: Bera
authors: Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States.
authors: Falguni
authors: F
authors: Das
authors: VA Research, South Texas Veterans Health Care System, San Antonio, TX, United States; Department of Pathology, University of Texas Health Science Center at San Antonio, Texas, United States.
authors: Nandini
authors: N
authors: Ghosh-Choudhury
authors: Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States; VA Research, South Texas Veterans Health Care System, San Antonio, TX, United States.
authors: Balakuntalam S
authors: BS
authors: Kasinath
authors: Department of Medicine, University of Texas Health Science Center at San Antonio Texas, United States; VA Research, South Texas Veterans Health Care System, San Antonio, TX, United States; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, United States. Electronic address: choudhuryg@uthscsa.edu.
authors: Goutam Ghosh
authors: GG
authors: Choudhury
mesh_terms: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D016415:Sequence Alignment; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C516104:Akt1s1 protein, rat; D002352:Carrier Proteins; D024042:Collagen Type I; C499526:Eif4ebp1 protein, rat; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; C556274:MIRN26 microRNA, rat; D035683:MicroRNAs; D046912:Multiprotein Complexes; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; D005947:Glucose
keywords: Diabetic nephropathy; Mesangial cell pathology; MicroRNA; mTOR