July 13, 2013 | by Darrin Joy
Cells govern their internal processes through highly complex signaling systems. A recent City of Hope study published in the journal Science Signaling shed more light on how cells control this system — and how diabetes can cause a malfunction that leads to kidney disease.
The study’s senior author, Rama Natarajan, Ph.D., director of the Division of Molecular Diabetes Research at City of Hope, explained the science published in their paper, “TGF-β Induces Acetylation of Chromatin and of Ets-1 to Alleviate Repression of miR-192 in Diabetic Nephropathy.”
What’s the main finding of this study?
MicroRNAs (miRNAs) are recently discovered small, noncoding RNAs that have been shown to affect the expression of genes and play pivotal roles in physiological and pathological processes. However, the mechanisms by which miRNAs are regulated are not fully understood.
Evidence shows that [a microRNA called] miR-192 is a key regulator of renal fibrosis and hypertrophy in diabetic nephropathy, a severe complication of diabetes. In this paper we showed that the miR-192 gene can be regulated by the concerted actions of a kinase called Akt and transcription factors Ets-1 and Smad3, as well as chromatin remodeling.
Under normal control conditions, Ets-1 binds to the miR-192 promoter and keeps the expression of miR-192 low. In response to a pathological growth factor, transforming growth factor–β (TGF-β) or high glucose stimulation to mimic diabetic conditions, Smad3 and Akt were activated. This led to activation of a chromatin acetylase called p300 resulting in acetylation and dissociation of Ets-1 and subsequent increased expression of miR-192.
During prolonged TGF-β treatment, p300 acetylated histones as well as Ets-1, resulting in complete dissociation of Ets-1 and the opening of the chromatin for sustained miR-192 expression.
Thus, transcription factors and chromatin remodeling control microRNA gene expression in a dynamic, coordinated fashion. In addition, in vivo relevance was noted because p300 activation and acetylation of Ets-1 and of histones were increased in diabetic db/db mice compared with wild-type mice, suggesting that alleviation of Ets-1 repression may contribute to diabetic nephropathy.
Why are these findings important?
Diabetic nephropathy is a major debilitating complication of diabetes for which there are very few effective drugs. Our results show that the initial activation of Akt kinase by TGF-β and diabetic conditions can trigger novel coordinated mechanisms that result in the downstream sustained activation of a key microRNA that contributes to the development of diabetic nephropathy.
These findings not only provide molecular insights into the regulation of miRNAs through signaling-mediated changes in transcription factor activity and in epigenetic histone acetylation under normal and disease states, but they also suggest new therapeutic options.
The Akt specific inhibitor, MK-2206, which is now used in treatment of cancer patients, inhibited induction of miR-192 and profibrotic genes such as collagens. MK-2206 or derivatives of the Akt inhibitor may be useful to treat kidney fibrosis in diabetic patients. Furthermore, based on our data, approaches for over-expressing Ets-1 could also be developed for renal protection under disease states.
What are the next steps for this line of research?
Establish new therapeutics for diabetic nephropathy by controlling miRNA expression via signal transduction pathways and transcription factors uncovered in this study.
Identify additional miRNAs that are involved in promoting or preventing diabetic nephropathy and also evaluate them as potential biomarkers for various stages of diabetic nephropathy.
This work was supported by National Institutes of Health grants R01 DK081705 and R01 DK058191.