Epigenetics and Diabetic Kidney Disease

This presentation was given by Peter Maxwell from Belfast HSC Trust and Queen’s University Belfast, Ireland. It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 1: Transcriptomics, Genomics and Epigenetics.

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Presentation Abstract:

Diabetic kidney disease is the commonest worldwide cause of end-stage renal disease. Multiple clinical risk factors for diabetic nephropathy are recognised including duration of diabetes, poor glycaemic control, hypertension and smoking.

An inherited susceptibility to diabetic kidney disease exists and this is likely to explain both the familial clustering of nephropathy and the differences in prevalence of kidney disease in different ethnic populations. Associations between individual genetic polymorphisms and diabetic kidney disease have been tested in multiple case-control studies (often with conflicting results). Larger scale genome wide association studies have identified a small number of genetic variants that have reached genome wide significance. These data do not fully explain why individuals with diabetes are susceptible to chronic kidney disease. Some of the “missing heritability” may be underpinned by epigenetic modifications within the genome.

Epigenetics refers to heritable (transgenerational) or dynamic changes in gene expression resulting from factors other than a direct change in the DNA sequence of the genome. These modifications may be inherited or occur in response to current or past environmental exposures such as diet, drugs or illness. Epigenetic mechanisms may include chromatin remodelling, altered DNA methylation or changes in the expression of specific microRNAs. Extreme environmental stress, e.g. intra-uterine growth retardation secondary to maternal starvation, may result in long term epigenetic modification of the genome with an increased lifetime risk of diabetes, cardiovascular disease or chronic kidney disease. Altered metabolic states, such as hyperglycaemia in diabetes, may lead to changes in gene expression mediated by epigenetic mechanisms and this has been referred to as hyperglycaemic “memory”.

Recent studies have started to determine how these specific epigenetic modifications are involved in the pathogenesis of kidney injury and progressive loss of renal function that characterises diabetic nephropathy. Epigenetic biomarkers could prove useful in stratifying those individuals at higher risk of developing diabetic kidney disease. Epigenetic features are also attractive therapeutic targets as they can be altered or reversed thus offering potential for drugs targeting epigenetic changes in specific kidney cells and tissues.