FOG2 protein down-regulation by transforming growth factor-ß1-induced microRNA-200b/c leads to Akt kinase activation and glomerular mesangial hypertrophy related to diabetic nephropathy.
J Biol Chem
; 288(31): 22469-80, 2013 Aug 02.
Article
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| MEDLINE
| ID: mdl-23788640
ABSTRACT
Glomerular hypertrophy is a hallmark of diabetic nephropathy. Akt kinase activated by transforming growth factor-ß1 (TGF-ß) plays an important role in glomerular mesangial hypertrophy. However, the mechanisms of Akt activation by TGF-ß 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-ß 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-ß-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-ß-treated MMC. Transfection of MMC with miR-200b/c mimics significantly decreased the expression of FOG2. Conversely, miR-200b/c inhibitors attenuated TGF-ß-induced decrease in FOG2 expression. Furthermore, miR-200b/c mimics increased the protein content/cell ratio, whereas miR-200b/c inhibitors abrogated the TGF-ß-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-ß-induced Akt activation through FOG2 down-regulation by miR-200b/c, which can lead to glomerular mesangial hypertrophy in the progression of diabetic nephropathy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Regulación hacia Abajo
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MicroARNs
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Nefropatías Diabéticas
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Proteínas de Unión al ADN
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Proteínas Proto-Oncogénicas c-akt
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Factor de Crecimiento Transformador beta1
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Mesangio Glomerular
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos