TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN

Abstract

How TGF-β activates Akt in disease situations is unclear. By acting on the promotor of RP23, a non-coding RNA which encodes two microRNAs, TGF-β signalling downregulates the phospatase PTEN, a target of these microRNAs and an inhibitor of Akt signalling. 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.