Epigenetics in diabetic kidney disease

Abstract

Regulated gene expression by transcription factor networks is critical for normal kidney function. Disruption of these complex networks leads to biochemical aberrations associated with many renal diseases. Epigenetic mechanisms not involving changes in DNA sequence, such as DNA methylation and post-translational modifications of nucleosomal histones, also play a critical role in gene regulation by modulating chromatin access to the cellular machinery for transcription. These epigenetic modifications can be affected by intrinsic and extrinsic environmental factors and play a central role in dictating biologic phenotypes including pathologic disease. Emerging evidence also suggests, apart from traditional genetic predisposition, that epigenetic processes can persist across generations to play a modulating role in the development of renal diseases such as diabetic nephropathy. Recent advances in epigenome research has increased our understanding of epigenetic mechanisms involved in renal dysfunction that in turn may lead to identification of novel new therapeutic targets.

Figure 1.

Epigenetic mechanisms can lead to the inhibition of protective genes and activation of pathologic genes associated with renal disease. Chromosomal DNA is tightly packed into higher order nucleoprotein complexes in chromatin consisting of repeating units of nucleosomes made up of DNA wrapped around dimers of core histone proteins. Epigenetic mechanisms including post-transcriptional modifications of nucleosomal histone amino-terminal tails, DNA methylation (DNAme), and noncoding RNAs, collectively referred to as the epigenome, regulate dynamic switching of chromatin between transcriptionally silent compact structure (heterochromatin) and active relaxed structure (euchromatin) to regulate gene expression. Histone lysine acetylation (H3/H4Kac) mediated by histone acetyl transferases such as CBP/P300 and H3 lysine 4 methylation (H3K4me) mediated by histone methyltransferases such as SET7 and MLL can lead to the formation of open chromatin accessible to transcription machinery and active gene expression. In contrast, histone PTMs such as H3K9me3, H3K27me3, and H4K20me3 mediated by HMTs Suv39h1, Ezh2, and Suv4h20, respectively, and DNAme mediated by DNA methyltransferases promote heterochromatin structure associated with transcriptional repression. These modifications are reversible by relevant histone deacetylases, histone demethylases, and DNA demethylases (not shown here). Alterations in the epigenome under disease states such as diabetes or renal injury leads to increased expression of pathologic inflammatory and fibrotic genes and microRNAs (miRNAs) involved in renal diseases or to the inhibition of protective genes. Furthermore, miRNAs can also target epigenetic components to mediate aberrant gene expression. Persistence of epigenetic alterations including decreased H3K9me3 or increased H4K20me3 or H3K4me in diabetes can play key roles in metabolic memory implicated in chronic vascular and renal complications that persist even after glycemic control. HG, high glucose; AGEs, advanced glycation end products; RNA Pol2, RNA polymerase II.