Abstract
Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane—a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.
Highlights
The worldwide prevalence of type 2 diabetes mellitus has rapidly increased over the past 30 years as a result of changes in the population distribution, namely, aging of the general population (Worldwide trends in diabe, 2016), indicating that the prevalence of microvascular complications, such as diabetic nephropathy (DN) and neuropathy and macrovascular complications, such as cardiovascular diseases, has increased (Liyanage et al, 2015; Shah and Brownlee, 2016; Yoshida et al, 2020)
We focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes
Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, has been reported to be one of the most important factors involved in the pathogenesis of diabetic nephropathy, which plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin
Summary
The worldwide prevalence of type 2 diabetes mellitus has rapidly increased over the past 30 years as a result of changes in the population distribution, namely, aging of the general population (Worldwide trends in diabe, 2016), indicating that the prevalence of microvascular complications, such as diabetic nephropathy (DN) and neuropathy and macrovascular complications, such as cardiovascular diseases, has increased (Liyanage et al, 2015; Shah and Brownlee, 2016; Yoshida et al, 2020). Based on the importance of podocytes in DKD and disease progression in epigenetic research, this review summarizes recent advances regarding epigenetic changes, especially altered DNA methylation in podocytes, and detection of these alterations in human diabetic nephropathy samples. The role of podocyte injury and adaptation in kidney function decline is consistent with a previous report showing the value of segmental sclerosis in predicting kidney function decline in diabetic kidney disease (Mottl et al, 2018) These results indicate that subtypes of podocyte changes in DKD, including podocyte hyperplasia and podocytopathy, may be interesting markers for disease progression as well as targets for podocyte-specific therapeutics. Methylation of cytosine in CpG islands, which are often found in or around the FIGURE 1 | Hyperglycemia induced DNA methylation changes in podocytes Gene expression such as nephrin, NEPH1 and RCAN1 is maintained with “active” promoter, which forms intact slit diaphragm. We have focused on DNA methylation in particular, but we would like to refer a few important recent
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