Abstract
Akt kinase is activated by transforming growth factor-β1 (TGF-β) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells1,2,3,4,5,6,7,8,9,10,11. However, the mechanisms of Akt activation by TGF-β are not fully understood. Here we show that TGF-β activates Akt in glomerular mesangial cells by inducing the microRNAs (miRNAs) miR-216a and miR-217, both of which target PTEN (phosphatase and tensin homologue), an inhibitor of Akt activation. These miRNAs are located within the second intron of a non-coding RNA (RP23-298H6.1-001). The RP23 promoter was activated by TGF-β and miR-192 through E-box-regulated mechanisms, as shown previously3. Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-β. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-β. Due to the diversity of PTEN function12,13, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.
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Acknowledgements
This work was supported by grants from the NIH-National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation (to RN). We are grateful to M. C.-T. Hu for a generous gift of plasmids (pFRE–Luc and FoxO3a–GFP), L.Wang and J. Arizala for technical assistance and S. DaCosta for editing the manuscript.
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M.K. and R.N. designed research; M.K., S.P., M.W., H.Y., L.L., I.N., A.G., and I.T. performed research; M.K., M.W., Y.N, H.S. and J.J.R. contributed new reagents/analytic tools; M.K., S.P. and I.T. analysed data and M.K. and R.N. wrote the paper.
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Kato, M., Putta, S., Wang, M. et al. TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat Cell Biol 11, 881–889 (2009). https://doi.org/10.1038/ncb1897
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DOI: https://doi.org/10.1038/ncb1897