Epigenetics and epigenomics in diabetic kidney disease and metabolic memory

Abstract

The development and progression of diabetic kidney disease (DKD), a highly prevalent complication of diabetes mellitus, is influenced by both genetic and environmental factors. DKD is an important contributor to the morbidity of patients with diabetes mellitus, indicating a clear need for an improved understanding of disease aetiology to inform the development of more efficacious treatments. DKD is characterized by an accumulation of extracellular matrix, hypertrophy, and fibrosis in kidney glomerular and tubular cells. Increasing evidence shows that genes associated with these features of DKD are regulated not only by classical signalling pathways, but also by epigenetic mechanisms, involving chromatin histone modifications, DNA methylation, and non-coding RNAs. These mechanisms can respond to changes in the environment and importantly, might mediate the persistent long-term expression of DKD-related genes and phenotypes induced by prior glycaemic exposure, despite subsequent glycaemic control, a phenomenon called metabolic memory. Detection of epigenetic events during the early stages of DKD could be valuable for timely diagnosis and prompt treatment to prevent progression to end-stage renal disease. Identification of epigenetic signatures of DKD via epigenome-wide association studies might also inform precision medicine approaches. Here, we highlight the emerging role of epigenetics and epigenomics in DKD, and the translational potential of candidate epigenetic factors and non-coding RNAs as biomarkers and drug targets for DKD.

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

“…In addition to transcription factors and classical signalling cascades, genes associated with DKD are regulated by epigenetic mechanisms . Epigenetic changes do not alter the underlying DNA sequence but affect the accessibility of chromatin and expression of genes via DNA methylation, chromatin histone modifications and non‐coding RNAs.…”

“…Environmental factors play a key role in the development of DKD, and the epigenetic mechanisms mediate the crosstalk between the genes and the environment. Epigenetic changes are also apparently involved in the so called metabolic memory, in which the gene expression pattern induced by high glucose persists even though the glycemic control has been achieved . The emerging developments in the epigenetic research in DKD may open new therapy options for DKD.…”

Dynamic changes in RNA-chromatin interactome promote endothelial dysfunction

“…the changes persist after the switch of hyperglycemia to normoglycemia which may underlie the persistent damage due to diabetic conditions (e.g. hyperglycemia and chronic inflammation) [43][44][45] . Interestingly, replenishing ECs with control media after 3 days of H+T treatment partially reversed the cell morphology change ( Figure S10A).…”

Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage

“…These studies have allowed researchers to build high-resolution maps of the chromatin structure and genome-wide distribution of epigenetic modifications at regulatory elements [37]. These technologies as well as the availability of archived DNA samples from various clinical trials have facilitated several epigenome-wide association studies (EWAS) that, in conjunction with genome-wide association studies (GWAS) studies, can shed new light on the causes of common diseases such as breast cancer [38].…”