MicroRNA-155 Regulates Human Angiotensin II Type 1 Receptor Expression in Fibroblasts

• Published in: The Journal of biological chemistry 2006-07, Vol.281 (27), p.18277-18284
• Main Authors: Martin, Mickey M., Lee, Eun Joo, Buckenberger, Jessica A., Schmittgen, Thomas D., Elton, Terry S.
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Angiotensin II - pharmacology; Animals; Binding Sites - genetics; Cells, Cultured; Enzyme Activation - genetics; Fibroblasts - metabolism; Gene Expression Regulation - drug effects; Humans; MicroRNAs - genetics; MicroRNAs - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Receptor, Angiotensin, Type 1 - biosynthesis; Receptor, Angiotensin, Type 1 - genetics; RNA Processing, Post-Transcriptional; RNA, Antisense - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - genetics; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M601496200

A large number of studies have demonstrated that the expression of the angiotensin II type 1 receptor (AT1R) is regulated predominantly by post-transcriptional mechanisms. Recently, it has been suggested that 10% of human genes may be regulated, in part, by a novel post-transcriptional mechanism involving microRNAs (miRNAs). miRNAs are small RNAs that regulate gene expression primarily through translational repression. The aim of this study was to determine whether miRNAs could regulate human AT1R expression. Luciferase reporter assays demonstrated that miR-155 could directly interact with the 3′-untranslated region of the hAT1R mRNA. Functional studies demonstrated that transfection of miR-155 into human primary lung fibroblasts (hPFBs) reduced the endogenous expression of the hAT1R compared with non-transfected cells. Additionally, miR-155 transfected cells showed a significant reduction in angiotensin II-induced extracellular signal-related kinase 1/2 (ERK1/2) activation. Furthermore, when hPFBs were transfected with an antisense miR-155 inhibitor, anti-miR-155, endogenous hAT1R expression and angiotensin II-induced ERK1/2 activation were significantly increased. Finally, transforming growth factor-β1 treatment of hPFBs resulted in the decreased expression of miR-155 and the increased expression of the hAT1R. In summary, our studies suggest that miR-155 can bind to the 3′-untranslated region (UTR) of hAT1R mRNAs and translationally repress the expression of this protein in vivo. Importantly, the translational repression mediated by miR-155 can be regulated by physiological stimuli.