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Review
. 2024 Oct 29;25(21):11599.
doi: 10.3390/ijms252111599.

Epigenetic DNA Methylation and Protein Homocysteinylation: Key Players in Hypertensive Renovascular Damage

Affiliations
Review

Epigenetic DNA Methylation and Protein Homocysteinylation: Key Players in Hypertensive Renovascular Damage

Lu Ren et al. Int J Mol Sci. .

Abstract

Hypertension has been a threat to the health of people, the mechanism of which, however, remains poorly understood. It is clinically related to loss of nephron function, glomerular sclerosis, or necrosis, resulting in renal functional declines. The mechanisms underlying hypertension's development and progression to organ damage, including hypertensive renal damage, remain to be fully elucidated. As a developing approach, epigenetics has been postulated to elucidate the phenomena that otherwise cannot be explained by genetic studies. The main epigenetic hallmarks, such as DNA methylation, histone acetylation, deacetylation, noncoding RNAs, and protein N-homocysteinylation have been linked with hypertension. In addition to contributing to endothelial dysfunction and oxidative stress, biologically active gases, including NO, CO, and H2S, are crucial regulators contributing to vascular remodeling since their complex interplay conducts homeostatic functions in the renovascular system. Importantly, epigenetic modifications also directly contribute to the pathogenesis of kidney damage via protein N-homocysteinylation. Hence, epigenetic modulation to intervene in renovascular damage is a potential therapeutic approach to treat renal disease and dysfunction. This review illustrates some of the epigenetic hallmarks and their mediators, which have the ability to diminish the injury triggered by hypertension and renal disease. In the end, we provide potential therapeutic possibilities to treat renovascular diseases in hypertension.

Keywords: DNA methylation; epigenetics; gaseous molecules; histone modification; kidney disease; metabolic disorder; noncoding RNA; protein homocysteinylation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Major mechanisms of epigenetic modification. DNA methylation is a covalent binding of a methyl group to 5′ carbon of cytosine (C) located at a CpG dinucleotide, which generally prevents a gene’s transcription when taking place in the gene promoter. Histone modifications are covalent post-translational alterations of N-terminal tails of four core histones, including H3, H4, H2A, and H2B, affecting gene expression by controlling the conformation and dynamics of chromatin. RNA interference refers to noncoding RNAs, including small noncoding RNAs (miRNAs) that have a downregulating influence on gene transcription by causing target mRNA degradation or by mRNA translational repression.
Figure 2
Figure 2
Epigenetic cellular modification and hypertension. Abbreviations: eNOS, endothelial nitric oxide synthase; ER-β, estrogen receptor-β; PCAF, P300/CBP-associated factor; SIRT1, Sirtuin 1; EcSOD, extracellular superoxide dismutase; HDAC, histone deacetylase; H3Ac, acetylated histone H3.
Figure 3
Figure 3
Hypertension-related kidney damages.
Figure 4
Figure 4
Metabolic disorders, hyperhomocysteinemia, and hypertension. HHcy: hyperhomocysteinemia, ROS: reactive oxygen species, NO: nitric oxide, 5-aza: 5-aza-2′-deoxycytidine, MMP-9: metalloproteinase-9.
Figure 5
Figure 5
Protein homocysteinylation and hypertension. Hcy: homocysteine, eNOS: endothelial nitric oxide synthase, CBS: cystathionine β-synthase, MTHFR: methylenetetrahydrofolate reductase.
Figure 6
Figure 6
Main functions of biologically active gases, NO, CO, and H2S, and their interaction. CBS, cystathionine-β-synthase; CSE, cystathionine-γ-lyase; HOs, heme oxygenases.

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