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Review
. 2021 Sep 24:12:759299.
doi: 10.3389/fphar.2021.759299. eCollection 2021.

Epigenetic Alterations in Podocytes in Diabetic Nephropathy

Erina Sugita  1 , Kaori Hayashi  1 , Akihito Hishikawa  1 , Hiroshi Itoh  1
Affiliations
Review

Epigenetic Alterations in Podocytes in Diabetic Nephropathy

Erina Sugita et al. Front Pharmacol. .

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.

Keywords: DNA damage repair; diabetic nephropathy; epigenetic memory; epigenetics; podocyte.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
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. Hyperglycemia induces DNA methylation of their promoter regions, which causes “silenced” promoter and decreased expression, leading disruption of the slit membrane. TET2 is a potential factor of podocyte protection through DNA demethylation of the nephrin and NEPH1 promoter regions in diabetes. KLF, Kruppel like factor; KAT5, lysine acetyltransferase 5; NEPH1, Nephrin-like protein 1; KDM6A, lysine demethylase 6A; RCAN1, regulator of calcineurin 1; DNMT1, DNA metyltransfearse 1; TET2, ten-eleven-translocation 2.
FIGURE 2
FIGURE 2
DNA damage repair in podocytes highlighting the epigenetic aspects. Exogenous or endogenous stress causes DNA damage in podocytes. When damaged, DNMT1 is recruited to DSB sites where it colocalizes with phosphorylated histone H2AX (y H2AX) to silence the repaired gene. Increased DNA methylation due to DNMT1 action may indicate epigenetic memory denoting former damage, which induces altered expressions of critical genes in podocytes. DNMT1, DNA metyltransfearse 1; DSB, double strand break; DNAme, DNA methylation.
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