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TGF‐beta activates Akt kinase and induces glomerular mesangial hypertrophy related to diabetic nephropathy through FOG2 inhibition by microRNA‐200b/c
Author(s) -
Park Jung Tak,
Kato Mitsuo,
Lanting Linda,
Putta Sumanth,
Castro Nancy,
Natarajan Rama
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.759.3
Subject(s) - protein kinase b , mesangial cell , endocrinology , medicine , transforming growth factor , diabetic nephropathy , transfection , chemistry , muscle hypertrophy , gene knockdown , signal transduction , cancer research , microbiology and biotechnology , biology , kidney , apoptosis , biochemistry , gene
Glomerular hypertrophy is a hallmark of diabetic nephropathy (DN). Akt kinase activated by transforming growth factor‐beta1 (TGF‐b) plays an important role in glomerular mesangial hypertrophy. However, the mechanisms of Akt activation by TGF‐b are not fully understood. Recently, miR‐200 and its target FOG2 were reported to regulate PI3‐Kinase (the upstream activator of Akt) activity in insulin signaling. Here we show that TGF‐b activates Akt in glomerular mesangial cells (MC) by inducing miR‐200b/c, both of which target FOG2, an inhibitor of Akt activation. FOG2 expression was reduced in diabetic mice glomeruli as well as TGF‐b treated mouse MC (MMC). FOG2 knockdown by siRNAs in MMC activated Akt and increased protein content/cell ratio suggesting hypertrophy. miR‐200b/c levels increased significantly in diabetic mice glomeruli and TGF‐b stimulated MMC. Transfection of MMC with miR‐200b/c mimics decreased the expression of FOG2. Conversely, TGF‐b induced decrease in FOG2 expression was attenuated by miR‐ 200b/c transfection into MMC. Furthermore, miR‐200b/c mimics increased the protein content/cell ratio, while miR‐200b/c inhibitors abrogated the TGF‐b induced increase in protein content/cell. These data suggest a new mechanism of Akt activation by TGF‐b through FOG2 down regulation by miR‐ 200b/c which can lead to MC hypertrophy in the progression of DN. (supported by NIH DK08170 and NIH DK058191)