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Liu, F.;  Chen, J.;  Li, Z.;  Meng, X. Epigenetics and Age-Related Kidney Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/24230 (accessed on 08 July 2025).
Liu F,  Chen J,  Li Z,  Meng X. Epigenetics and Age-Related Kidney Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/24230. Accessed July 08, 2025.
Liu, Feng, Jiefang Chen, Zhenqiong Li, Xian-Fang Meng. "Epigenetics and Age-Related Kidney Diseases" Encyclopedia, https://encyclopedia.pub/entry/24230 (accessed July 08, 2025).
Liu, F.,  Chen, J.,  Li, Z., & Meng, X. (2022, June 20). Epigenetics and Age-Related Kidney Diseases. In Encyclopedia. https://encyclopedia.pub/entry/24230
Liu, Feng, et al. "Epigenetics and Age-Related Kidney Diseases." Encyclopedia. Web. 20 June, 2022.
Epigenetics and Age-Related Kidney Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/genes13050796

The main types of epigenetic processes including DNA methylation, histone modifications, non-coding RNA (ncRNA) modulation have all been implicated in the progression of age-related kidney diseases, and therapeutic targeting of these processes will yield novel therapeutic strategies for the prevention and/or treatment of age-related kidney diseases.

epigenetics kidney diseases DNA

1. Introduction

Currently, the mechanisms responsible for age-related decline in organ function have not been fully understood, but growing evidence suggests that epigenetic alterations, primarily including aberrant DNA methylation, histone post-translational modifications, and regulation by ncRNAs, play an important role in various age-related human disorders such as neurodegenerative [1], cardiovascular diseases [2], and degenerative spinal stenosis [3] as well as various kidney diseases [4][5]. 

2. DNA Methylation in Age-Related Renal Diseases

Although covalent modifications of DNA bases had been described since 1948 by Hotchkiss [6], it was not until 1969 that Griffith and Mahler proposed that these modifications may involve the modulation of gene expression [7]. In particular, the major modification in eukaryote DNA is 5-methylcytosine (5mC) [8], which primarily occurs at the fifth position of the pyrimidine ring of cytosines. DNA methylation, the first identified epigenetic mechanism, which occurs primarily at cytosine-phosphate-guanine (CpG) dinucleotides within the gene promoter regions [9], is involved in regulating gene expression through inhibiting specific transcription factors binding to DNA or recruiting mediators of chromatin remodeling (e.g., histone-modifying enzymes) [10][11][12][13]. In mammals, DNA methylation patterns are routinely established and maintained by three DNA methyltransferases (DNMT) [13][14] including DNMT1, DNMT3a, and DNMT3b, while in contrast, DNA demethylation can be achieved by the ten-eleven translocation (TET) enzymes through converting 5mC to 5-hydroxymethylcytosine (5hmC) [15][16].
The dynamic regulation of DNA methylation and demethylation is one of the most important epigenetic regulatory mechanisms in eukaryotic cells, which up to now, has not been fully understood. Increasing evidence has demonstrated that aberrant DNA methylation of specific CpG sites may serve as sensitive biomarkers to identify individuals at risk for age-related diseases [3][17]. In particular, age-related renal diseases such as CKD and ESRD are a major public health problem worldwide for its high morbidity among aging populations. Several studies have well explored the associations between DNA methylation patterns and age-related kidney diseases [18][19][20]. For instance, a recent study investigated the genome-wide changes in DNA methylation in renal biopsy samples obtained from 95 healthy kidney donors aged from 16 to 73 years old [21]. A total of 92,778 CpG methylation sites were identified to be significantly associated with donor age through the analysis of genome-wide changes in DNA methylation (more than 800,000 CpG sites) (FDR <0.05), corresponding to 10,285 differentially methylated regions. Interestingly, these regions were most frequently located in the Wnt/β-catenin signaling pathway related genes including the dickkopf Wnt signaling inhibitors (DKK), several SOX transcription factors, Wnt inhibitory factor 1 (WIF1), secreted frizzled related protein 2 (SFRP2), retinoic acid receptor alfa and beta (RARA and RARB), and so on. Hypermethylation in the promoter region of these Wnt signaling inhibitor genes may contribute to the activation of Wnt/β-catenin signaling in aged kidney. Furthermore, Wnt/β-catenin signaling, a conserved signaling pathway in organ development, is kept silent in normal adult kidneys [22][23], which is reactivated predominately in tubular epithelial cells in a variety of CKD models [24]. Thus, hypermethylation of these Wnt signaling inhibitor genes induce activation of Wnt/β-catenin signaling, which may lead to aging-related renal changes by triggering tubular epithelial cell transition to mesenchymal or senescent phenotype and promoting renal fibrosis. This research clearly revealed a causal relationship between DNA hypermethylation and age-associated renal dysfunction [21], indicating that DNA methylation alterations could be a new class of potential non-invasive diagnostic and prognostic biomarkers for age-related kidney diseases. Moreover, numerous clinical observations and animal studies have demonstrated that DNA methylome alterations are implicit in the development and progression of CKD [25][26][27][28]. For example, an epigenome-wide association study (EWAS) was performed to investigate the genome-wide methylation profiles in whole blood samples from 4859 aging adults, which demonstrated that the epigenetic signatures were significantly associated with kidney function and CKD as well as with the clinical endpoint renal fibrosis [28]. The researchers identified 19 CpG sites associated with eGFR and CKD from whole blood samples, among which five CpG sites were associated with renal fibrosis and showed consistent and significant DNA methylation changes in renal cortical biopsy samples from CKD patients. The study revealed that eGFR-associated CpG sites were significantly enriched in regions bound to serval transcription factors including Early B-cell Factor1 (EBF1), E1A Binding Protein P300 (EP300), and CCAAT/enhancer-binding protein beta (CEBPB), highlighting the impact of epigenetic modifications on renal function. Moreover, previous studies have demonstrated that several targeted genes regulated by CEBPB, EBF1, and EP300 are essential for kidney development and function [29][30][31][32], suggesting that methylation alterations of CEBPB, EBF1, and EP300 target genes may block the regulation of CEBPB, EBF1, and EP300 on their target genes, leading to the development of CKD. Thus, CEBPB, EBF1, and EP300 may serve as promising candidates for future experimental studies to illuminate the underlying gene regulatory mechanisms linking differential DNA methylation to kidney function in health and disease.
Despite several genome-wide association studies and epigenome-wide association studies having identified significant changes in DNA methylation with aging and age-related kidney diseases, there is currently still a lack of a direct evidence indicating that alterations in particular gene expression patterns as well as gene-specific DNA methylation influence renal aging [33][34]. A more recent study has provided strong evidence for uncovering important epigenetic features of kidney aging [33]. Recently, Gao and colleagues reported that chronic injection of D-galactose (D-gal)-induced aging or natural aging kidneys led to significant inhibition of KLOTHO and antiaging factor nuclear factor erythroid-derived 2-like 2 (NRF2) expression, accompanied by increased expression of DNMTs (subtypes of DNMT1, DNMT3a, and DNMT3b) as well as hypermethylation of NRF2 and KLOTHO gene promoter [33]. Administration of DNA-demethylating agent, SGI-1027 and OLP, effectively reduced DNA methylation of the NRF2 and KLOTHO promoter and alleviated D-gal-induced aging-related structural and functional alteration changes in mouse kidney. Notably, the anti-renal aging effects of SGI-1027 in D-gal-induced aging mice were significantly abolished by silencing KLOTHO in vivo. Researchers can conclude that dysregulation of DNMT1/3a/3b significantly contributes to the kidney aging process and epigenetic intervention with DNA-demethylating agents can mitigate renal aging alterations, suggesting that alteration of particular gene expression patterns and genomic DNA methylation can indeed influence the renal aging process. Thus, developing therapeutic strategies aimed at reversing age-associated adverse epigenetic changes will contribute to the development of novel therapeutic interventions that can delay or alleviate renal aging and age-associated kidney disorders.
From current research on DNA methylation in age-related kidney diseases (Table 1), researchers can conclude that DNA methylation might have exerted critical regulatory functions in both normal renal aging and age-related kidney diseases. Nevertheless, the present studies are far from sufficient to elucidate the molecular mechanisms underlying DNA methylation changes in age-related kidney diseases. Furthermore, most of these investigations lack in vivo experimental validation. Therefore, more systematic studies focused on DNA methylation alterations in age-related kidney diseases and clinical applications are required in the future.
Table 1. DNA methylation in age-related kidney diseases.
Allele Sample Dysregulation Target Brief Role Reference
DNMT1
DNMT3a
DNMT3b		 Mice (2–25 months) Upregulated KLOTHO, NRF2 Aberrant DNMT1/3a/3b elevations resulting in the promoter hypermethylation and expression suppressions of KLOTHO and NRF2, which accelerate renal fibrosis in D-gal-induced aging. [33]
DNMTs Mice (12–14 and 75–78 weeks) Upregulated SODs,
Sirt1,
Nox4		 Hypermethylation of antioxidant enzymes induced by DNMTs in the aged kidney during hypertension worsens redox imbalance leading to kidney damage. [34]

3. Altered Balance of Histone Modifications in Age-Related Renal Diseases

Genomic information of eukaryotic cells is mainly deposited in nuclear chromatin, which consists of DNA, RNA, histones, and non-histone proteins [35][36]. In particular, the chromatin displays two very different states: euchromatin and heterochromatin [37][38], in which the former is loosely packed and transcriptionally active while the latter is tightly packed and less transcriptionally active. The histone octamer is composed of two histone H2A–H2B heterodimers and one H3–H4 tetramer, which is encapsulated by approximately 147 bp of DNA to form the nucleosome [39]. Histones are composed of a central globular domain and flexible charged N-terminal tails. Because the NH2 terminus of histones extend from the core and contain specific amino acid residues, they are highly susceptible to multiple types of post-translational modifications such as acetylation, phosphorylation, ubiquitination, SUMOylation, and methylation, thereby affecting their function [37][40][41]. Notably, histone modifications can directly affect chromatin structure through preventing the binding of transcription factors to their specific binding sites or altering the interaction between histone tails and nucleosome DNA, which play critical roles in the regulation of gene expression [42][43]. For instance, a number of genome-wide studies have indicated that histone modifications in a specific genomic region can contribute to changes in chromatin structure, leading to either the activation or repression of specific gene expression [44][45][46].
Histone modification alterations have been reported to influence a wide variety of biological processes (e.g., cell growth, cell differentiation, threonine metabolism, and inflammation [47][48][49][50]) that positively or negatively affect the development of aging. Growing evidence supports the idea that histone modifications have greatly increased people's knowledge regarding epigenetic modifications in the expression of many genes during the development of renal aging [51][52]. When it comes to age-related kidney diseases, the most prevalent reported and best characterized type of histone modifications are histone acetylation/deacetylation [53], which are dynamically regulated by two families of enzymes with opposing roles: histone acetyltransferases (HATs) and histone deacetylases (HDACs) [54]. Many acetylation signs on histones typically reduce with age, mainly including H3 acetylation on lysine 18, 27, and 56 as well as bulk H4 acetylation, which are considered to contribute to the aging process and the development of age-related diseases [55]. At present, mammalian HDACs are divided into four categories according to their homology with yeast [56] including class I (HDAC1, 2, 3, 8), class II a (HDAC4, 5, 7, and 9), class II b (HDAC6 and 10), class III (Sirtuins, Sirt1-7), class IV (HDAC11), of which class I, II and IV HDACs are dependent upon Zn2+ as a cofactor and sensitive to all HDAC inhibitors, while class III HDACs rely on NAD+ for their activities and are insensitive to classical HDAC inhibitors [57]. Generally, HDACs can deacetylate lysine residues on histone tails, which restore the positive charges of chromatin histones, leading to the condensation of chromatin and inhibition of gene transcription. Emerging studies have indicated the aberrant expression of HDACs is closely associated with renal aging and age-related kidney diseases [53][58]. Moreover, accumulating evidence also suggests that HDAC inhibitors can beneficially modulate age-related processes, probably by reversing age-related deacetylation of chromatin, acetylation of histones near pro-longevity genes, activating pro-longevity proteins, and/or de-activating anti-longevity proteins [55][59], which still needs to be further investigated.
Histone deacetylase 3 (HDAC3), a member of class I HDAC family, is critical for mammalian embryonic development and the aging process. The aberrant activation of HDAC3 is closely linked to a wide variety of human disease such as cancer [60], diabetes mellitus [61][62], neurodegenerative disorders [63], and CKD [64]. For instance, NM_026333, a newly discovered anti-aging gene, was identified to be obviously downregulated in the kidneys from coupling factor 6 (CF6)-overexpressing transgenic and high salt-fed mice present with premature aging-like phenotypes [65]. Endogenous overexpression of NM_026333 or supplementation of NM_026333 recombinant protein alleviated CF6-induced senescence characteristics of HEK-293 cells (e.g., impaired autophagy, genomic instability, and epigenetic alterations) through abolishing HDAC3-induced transcriptional repression of autophagy related 7 (Atg7), suggesting that HDAC3 can accelerate renal aging by impairing autophagy [65]. Moreover, HDAC3 has been indicated to inhibit the transcription of Klotho, a well-known anti-aging protein, in various kidney diseases such as CKD [64] and renal fibrotic disorders [66]. Targeting Klotho loss through HDAC3 inhibition may serve as a new strategy for anti-renal fibrosis therapies as well as promising therapeutic potential for a reduction in CKD progression. These studies together indicate that aberrant activation of HDAC3 likely contributes to age-related kidney diseases, however, whether target inhibition of HDAC3 might mitigate renal aging as well as prevent and treat age-related kidney diseases remains to be further investigated.
Sirts, a conserved family composed of seven members (Sirt1-7), belong to class III NAD+-dependent HDACs, which have been considered as a class of critical regulators of aging and metabolic disease [67]. Sirts are widely expressed in various types of kidney cells, some of which have been demonstrated to delay renal aging. The expression of Sirt1 was significantly decreased in aging kidneys, which was associated with changes in the expression of a variety of target molecules (e.g., Klotho [68], peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) [69], forkhead box O3 (FOXO3) [69][70], AMP-activated protein kinase (AMPK) [71], and hypoxia-inducible factor-1α (HIF-1α) [72]). For example, podocyte-specific silencing of Sirt1 was found to exacerbate age-related glomerulosclerosis and albuminuria [69]. Endothelial Sirt1 deficiency contributes to nephrosclerosis through the downregulation of matrix metalloproteinase-14 (MMP-14), which is primarily associated with vascular aging and fibrosis [73] while pharmacological activation of Sirt1 significantly decreased the pathologic changes of aging in the kidney via activation of AMPK and the PPARα signaling pathway [71]. Consequently, Sirt1 is considered as a potential therapeutic target to treat age-related kidney diseases. Sirt3, a critical regulator of cell senescence, is related to renin-angiotensin-aldosterone system (RAAS) activation, which has been reported to play an important role in renal aging. Previous study has shown that targeted knockout of the Agtr1a (Agtr1a−/−) gene encoding Ang II type 1 receptors (AT1R) significantly extend the life span of mice, which is attributed to the attenuation of oxidative stress and the upregulation of Nampt and Sirt3 [74]. However, one more recent study by Uneda et al. has reported conflicting results and indicates that it is Sirt1, but not Sirt3, that is significantly decreased in the kidneys of aged Agtr1a−/− mice [75]. Although the critical function of Sirt3 in the renal aging process through the Ang II-AT1R signaling pathway remains controversial, Sirt3−/− mice develop more serious renal fibrosis than their age matched wild-type (WT) littermate controls as they age [76]. Altogether, these results suggest that Sirt3 does indeed play an important role in ameliorating age-related kidney diseases possibly through the attenuation of oxidative stress and the maintenance of mitochondrial integrity. In addition, the participation of Sirt6 has also been indicated to ameliorate age-related kidney damage through the suppression of the pro-inflammatory nuclear factor kappa-B (NF-Κb) signaling pathway [77]. Sirt6 deficiency significantly results in the progression of glomerular injury in aged mice kidney [78]. Taken together, current findings suggest that Sirts ameliorates the degree of tissue damage and fibrosis in the aging kidneys, probably through decreasing oxidative stress and inflammation, indicating that Sirts has great potential as novel therapeutic targets for the prevention and clinical treatment of age-related kidney diseases. Thus, great efforts toward demonstrating that Sirt activators are of great beneficial to patients would yield major clinical and public health implications.
In general, the above research demonstrates the underlying roles of histone acetylation and deacetylation in modulating renal aging and age-related renal diseases (Table 2). However, these studies provided limited insight into delineating specific molecular mechanisms, and direct evidence from in vivo studies supporting abnormal histone modifications patterns that contribute to age-related renal disease is lacking. Thus, continued efforts are still needed to elucidate the role of histone modifications in the field of age-related renal disorders.
Table 2. Histone modifications in age-related kidney diseases.
Allele Sample Dysregulation Target Brief Role Reference
HDAC3 HDAC3 knockout mice Upregulated Klotho Aberrant HDAC3 induction contributes to renal fibrogenesis through inhibiting Klotho, a renal epithelium-enriched aging suppressor. [66]
Sirt1 Mice (5, and 26–28 months) Downregulated PGC1α, FOXO3/4,
NF-κB		 Podocyte-specific Sirt1 knockdown accelerates kidney injury in aging mice through Sirt1-mediated deacetylation of downstream targets. [69]
Sirt1 Mice (3 and 24 months) Downregulated FOXO3 Long-term calorie restriction-induced upregulation of Sirt1 in aged kidney attenuated hypoxia-associated mitochondrial and renal damage by enhancing Bnip3-dependent autophagy. [70]
Sirt1 Mice (24 months) Downregulated AMPK and PPARα
signaling		 Pharmacological activation of Sirt1 by resveratrol attenuates age-related renal injury through activation of AMPK and PPARα signaling. [71]
Sirt1 Mice (5 weeks and 24 months) Downregulated HIF-1α Sirt1-induced deacetylation of HIF-1α may have protective effects against tubulointerstitial damage in aged kidney. [72]
Sirt1 Mice (12 weeks and 15 months) Not mentioned MMP-14 Endothelial Sirt1 deficiency contributes to nephrosclerosis through downregulation of MMP-14, which is primarily associated with vascular aging and fibrosis. [73]
Sirt1 Mice (3–4, 11–12, and 22–25 months) Down-regulated Not mentioned Angiotensin II type 1 receptor-associated protein (ATRAP) plays an important role in inhibiting kidney aging, possibly through sirt1-mediated inhibition of oxidative stress. [75]
Sirt3 Mice (15 months WT and
Sirt3-KO)		 Downregulated Glycogen synthase kinase-3 beta (GSK3β) Sirt3 blocks aging-associated renal fibrosis through deacetylating and activating GSK3β. [76]
Sirt6 Mice (6 and 24 months) Downregulated NF-kB
signaling		 CR-induced Sirt6 activation delays age-dependent renal degeneration through suppressing the NF-kB signaling pathway. [77]
Sirt6 Mice (1, 2, 7 months WT and Sirt6-KO) Downregulated Unknown Sirt6 deficiency results in progression of glomerular injury in the aged mice kidney [78]

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Subjects: Urology & Nephrology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Feng Liu
,
Jiefang Chen
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zhenqiong Li
,
Xian-Fang Meng
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Update Date: 22 Jun 2022
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