title: FOG2 protein down-regulation by transforming growth factor-β1-induced microRNA-200b/c leads to Akt kinase activation and glomerular mesangial hypertrophy related to diabetic nephropathy.
abstract: Glomerular hypertrophy is a hallmark of diabetic nephropathy. Akt kinase activated by transforming growth factor-β1 (TGF-β) plays an important role in glomerular mesangial hypertrophy. However, the mechanisms of Akt activation by TGF-β are not fully understood. Recently, miR-200 and its target FOG2 were reported to regulate the activity of phosphatidylinositol 3-kinase (the upstream activator of Akt) in insulin signaling. Here, we show that TGF-β activates Akt in glomerular mesangial cells by inducing miR-200b and miR-200c, both of which target FOG2, an inhibitor of phosphatidylinositol 3-kinase activation. FOG2 expression was reduced in the glomeruli of diabetic mice as well as TGF-β-treated mouse mesangial cells (MMC). FOG2 knockdown by siRNAs in MMC activated Akt and increased the protein content/cell ratio suggesting hypertrophy. A significant increase of miR-200b/c levels was detected in diabetic mouse glomeruli and TGF-β-treated MMC. Transfection of MMC with miR-200b/c mimics significantly decreased the expression of FOG2. Conversely, miR-200b/c inhibitors attenuated TGF-β-induced decrease in FOG2 expression. Furthermore, miR-200b/c mimics increased the protein content/cell ratio, whereas miR-200b/c inhibitors abrogated the TGF-β-induced increase in protein content/cell. In addition, down-regulation of FOG2 by miR-200b/c could activate not only Akt but also ERK, which was also through PI3K activation. These data suggest a new mechanism for TGF-β-induced Akt activation through FOG2 down-regulation by miR-200b/c, which can lead to glomerular mesangial hypertrophy in the progression of diabetic nephropathy.
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Jung Tak
authors.initials: JT
authors.lastname: Park
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kato
authors.forename: Hang
authors.initials: H
authors.lastname: Yuan
authors.forename: Nancy
authors.initials: N
authors.lastname: Castro
authors.forename: Linda
authors.initials: L
authors.lastname: Lanting
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003928:Diabetic Nephropathies / Q000473:pathology*; D015536:Down-Regulation; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D005920:Glomerular Mesangium / Q000473:pathology*; D006984:Hypertrophy / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C492170:Zfpm2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Cell Signaling; Diabetes; FOG2; Hypertrophy; MicroRNA; Nephrology; Transforming Growth Factor β (TGFbeta)