TGF-β induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy.

Abstract

MicroRNAs (miRNAs), such as miR-192, mediate the actions of transforming growth factor-β1 (TGF-β) related to the pathogenesis of diabetic kidney diseases. We found that the biphasic induction of miR-192 expression by TGF-β in mouse renal glomerular mesangial cells initially involved the Smad transcription factors, followed by sustained expression that was promoted by acetylation of the transcription factor Ets-1 and of histone H3 by the acetyltransferase p300, which was activated by the serine and threonine kinase Akt. In mesangial cells from Ets-1-deficient mice or in cells in which Ets-1 was knocked down, basal amounts of miR-192 were higher than those in control cells, but sustained induction of miR-192 by TGF-β was attenuated. Furthermore, inhibition of Akt or ectopic expression of dominant-negative histone acetyltransferases decreased p300-mediated acetylation and Ets-1 dissociation from the miR-192 promoter and prevented miR-192 expression in response to TGF-β. Activation of Akt and p300 and acetylation of Ets-1 and histone H3 were increased in glomeruli from diabetic db/db mice compared to nondiabetic db/+ mice, suggesting that this pathway may contribute to diabetic nephropathy. These findings provide insight into the regulation of miRNAs through signaling-mediated changes in transcription factor activity and in epigenetic histone acetylation under normal and disease states.

• Authors: Mitsuo Kato, Varun Dang, Mei Wang, Jung Tak Park, Supriya Deshpande, Swati Kadam, Armen Mardiros, Yumei Zhan, Peter Oettgen, Sumanth Putta, Hang Yuan, Linda Lanting, Rama Natarajan
• Journal: Science signaling (Sci Signal) Vol. 6 Issue 278 Pg. ra43 (Jun 04 2013) ISSN: 1937-9145 [Electronic] United States
• PMID: 23737551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• MIRN92 microRNA, human
• MicroRNAs
• Transcription Factors
• Transforming Growth Factor beta

Topics

• Acetylation
• Chromatin (physiology)
• Diabetic Nephropathies (physiopathology)
• Humans
• MicroRNAs (genetics, physiology)
• Transcription Factors (metabolism)
• Transforming Growth Factor beta (physiology)