Effects of metabolic memory on inflammation and fibrosis associated with diabetic kidney disease: an epigenetic perspective

Abstract

Diabetic kidney disease (DKD) is one of the most common microvascular complication of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM), and the leading cause of end-stage renal disease (ESRD) worldwide. Persistent inflammation and subsequent chronic fibrosis are major causes of loss of renal function, which is associated with the progression of DKD to ESRD. In fact, DKD progression is affected by a combination of genetic and environmental factors. Approximately, one-third of diabetic patients progress to develop DKD despite intensive glycemic control, which propose an essential concept “metabolic memory.” Epigenetic modifications, an extensively studied mechanism of metabolic memory, have been shown to contribute to the susceptibility to develop DKD. Epigenetic modifications also play a regulatory role in the interactions between the genes and the environmental factors. The epigenetic contributions to the processes of inflammation and fibrogenesis involved in DKD occur at different regulatory levels, including DNA methylation, histone modification and non-coding RNA modulation. Compared with genetic factors, epigenetics represents a new therapeutic frontier in understanding the development DKD and may lead to therapeutic breakthroughs due to the possibility to reverse these modifications therapeutically. Early recognition of epigenetic events and biomarkers is crucial for timely diagnosis and intervention of DKD, and for the prevention of the progression of DKD to ESRD. Herein, we will review the latest epigenetic mechanisms involved in the renal pathology of both type 1 (T1DN) and type 2 diabetic nephropathy (T2DN) and highlight the emerging role and possible therapeutic strategies based on the understanding of the role of epigenetics in DKD-associated inflammation and fibrogenesis.

Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria

“…The interest in epigenetic modifications in DN has in part been driven by their potential role in the phenomenon of “metabolic memory,” whereby individuals with diabetes and long-term normoglycemia (>25 years) still have an increased risk of DN due to poor glucose control in the past ( 97 ). There is increasing evidence that epigenetic changes are associated with DN ( 98 ). Although the majority of epigenetic studies concern nuclear DNA modifications, mitoepigenetics also has an important role in a variety of diseases, including cardiovascular disease, obesity, and diabetes ( 99 ).…”

A gastro-resistant peptide from Momordica charantia improves diabetic nephropathy in db/db mice via its novel reno-protective and anti-inflammatory activities

“…15 Recent studies indicated that DN is a chronic inflammatory immune disorder. 16–18 Crosstalk between cellular metabolic functions and immune activation (immune-metabolism) induces the infiltration of inflammatory cells into the kidneys, contributing to the progression of chronic kidney diseases and the decline in the glomerular filtration rate. 19,20 Structural and functional disorders of renal failure are strongly related to the overproduction of proinflammatory mediators, suggesting that inflammatory responses play crucial roles in the pathophysiology of DN.…”

Serum Amyloid A3 Promoter-Driven Luciferase Activity Enables Visualization of Diabetic Kidney Disease

“…Fibro-inflammatory cues are the cardinal molecular signals that drive DN pathogenesis and progression [1,[6][7][8][9]29,30]. Notably, several studies have shown that serum amyloid A (Saa) is a key potential mediator of danger signals that influence inflammatory processes in several chronic inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, obesity, and kidney diseases [17,[31][32][33][34].…”