Epigenetic mechanisms of salt-sensitive hypertension

Abstract

Salt-sensitive hypertension (SSH) is a complex and heterogeneous phenotype characterized by an abnormal blood pressure response to dietary salt intake. While genetic factors have been extensively explored, emerging evidence highlights the pivotal role of epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNAs) in modulating gene expression without altering the DNA sequence. These modifications respond dynamically to environmental stimuli such as diet, aging, stress and prenatal conditions, contributing to both the development and progression of SSH. This review summarizes current knowledge on the epigenetic regulation of genes involved in sodium handling, vascular tone and inflammation, focusing on pathways such as the renin-angiotensin-aldosterone system, the Klotho-Wnt5a-RhoA axis and the influence of the intrauterine environment. Special attention is given to transgenerational epigenetic inheritance and aging-related changes, as well as the reversibility of some epigenetic marks through lifestyle interventions such as salt restriction and physical activity. Understanding the interplay between environmental exposures and epigenetic regulation offers a new frontier for precision medicine in hypertension, but despite the promising findings, SSH-specific human data remain limited and a unifying epigenetic signature distinguishing SSH from other hypertensive phenotypes has yet to be defined. Further longitudinal studies and biomarker discovery efforts are needed to translate these insights into personalized preventive and therapeutic strategies.

Keywords: ageing; environment; epigenetics; salt-sensitive hypertension; transgenerational inheritance.

Graphical Abstract

Figure 1:

Mechanisms of epigenetic regulation in SSH: histone modifications, DNA methylation and non-coding RNA modulation. Histone modifications: KDM5A induces H3K4me1 enrichment and H3K9me2 depletion at the ACE1 promoter, leading to ACE1 upregulation. Aldosterone-activated SGK1 disrupts Af9-Dot1a interaction, reducing H3K79me3 at the ENaC promoter, resulting in ENaC upregulation. DNA methylation: the cg09680149 site is associated with SCNN1A, cg00805360 with ADAM8 and cg00574958 with CPT1A, thus influencing expression of these genes in hypertension. Non-coding RNA (miRNA/lncRNA) modulation: miR-429 impairs PHD2 mRNA expression, miR-155-5p decreases Far1 levels and lncRNA MALAT1 modulates the Keap1-Nrf2 antioxidant pathway in hypertension. ACE1: angiotensin-converting enzyme 1; ADAM8: metallopeptidase domain 8; CPT1A: carnitine palmitoyltransferase 1A; ENaC: epithelial sodium channel; Far1: fatty acyl CoA reductase 1; KDM5A: lysine-specific demethylase 5A; H3K4me1: histone H3 lysine 4 methylation; H3K9me2: histone H3 lysine 9 dimethylation; H3K79me3: histone H3 lysine 9 trimethylation; lncRNA: long non-coding RNA; MALAT1: metastasis-associated lung adenocarcinoma transcript 1; miRNA: microRNA; PHD2: prolyl-hydroxylase 2; SCNN1A: SGK1: serum/glucocorticoid regulated kinase 1.