Diabetic nephropathy: The regulatory interplay between epigenetics and microRNAs

Diabetic nephropathy (DN) is still one of the leading causes of end-stage renal disease despite the emergence of different therapies to counter the metabolic, hemodynamic and fibrotic pathways, implicating a prominent role of genetic and epigenetic factors in its progression. Epigenetics is the study of changes in the expression of genes which may be inheritable and does not involve a change in the genome sequence. Thrust areas of epigenetic research are DNA methylation and histone modifications. Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) control the expression of genes via post-transcriptional mechanisms. However, the regulation by epigenetic mechanisms and miRNAs are not completely distinct. A number of emerging reports have revealed the interplay between epigenetic machinery and miRNA expression, particularly in cancer. Further research has proved that a feedback loop exists between miRNA expression and epigenetic regulation in disorders including DN. Studies showed that different miRNAs (miR-200, miR-29 etc.) were found to be regulated by epigenetic mechanisms viz. DNA methylation and histone modifications. Conversely, miRNAs (miR-301, miR-449 etc.) themselves modulated levels of DNA methyltranferases (DNMTs) and Histone deacetylases (HDACs), enzymes vital to epigenetic modifications. With already few FDA approved epigenetic -modulating drugs (Vorinostat, Decitabine) in the market and miRNA therapeutic drugs under clinical trial it becomes imperative to analyze the possible interaction between the two classes of drugs in the modulation of a disease process. The purpose of this review is to articulate the interplay between miRNA expression and epigenetic modifications with a particular focus on its impact on the development and progression of DN.