TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN.
Akt kinase is activated by transforming growth factor-beta1 (TGF-beta) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells. However, the mechanisms of Akt activation by TGF-beta are not fully understood. Here we show that TGF-beta 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-beta and miR-192 through E-box-regulated mechanisms, as shown previously. Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-beta. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-beta. Due to the diversity of PTEN function, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.
Kato
Mitsuo
M
Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. mkato@coh.org
Putta
Sumanth
S
Wang
Mei
M
Yuan
Hang
H
Lanting
Linda
L
Nair
Indu
I
Gunn
Amanda
A
Nakagawa
Yoshimi
Y
Shimano
Hitoshi
H
Todorov
Ivan
I
Rossi
John J
JJ
Natarajan
Rama
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D006984:Hypertrophy / Q000139:chemically induced; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase