Epigenetic Modifications in T Cells

Abstract

The SS (Dahl salt sensitive) rat is an established model of hypertension and renal damage that is accompanied with immune system activation in response to a high-salt diet. Investigations into the effects of sodium-independent and dependent components of the diet were shown to affect the disease phenotype with SS/MCW (JrHsdMcwi) rats maintained on a purified diet (AIN-76A) presenting with a more severe phenotype relative to grain-fed SS/CRL (JrHsdMcwiCrl) rats. Since contributions of the immune system, environment, and diet are documented to alter this phenotype, this present study examined the epigenetic profile of T cells isolated from the periphery and the kidney from these colonies. T cells isolated from kidneys of the 2 colonies revealed that transcriptomic and functional differences may contribute to the susceptibility of hypertension and renal damage. In response to high-salt challenge, the methylome of T cells isolated from the kidney of SS/MCW exhibit a significant increase in differentially methylated regions with a preference for hypermethylation compared with the SS/CRL kidney T cells. Circulating T cells exhibited similar methylation profiles between colonies. Utilizing transcriptomic data from T cells isolated from the same animals upon which the DNA methylation analysis was performed, a predominant negative correlation was observed between gene expression and DNA methylation in all groups. Lastly, inhibition of DNA methyltransferases blunted salt-induced hypertension and renal damage in the SS/MCW rats providing a functional role for methylation. This study demonstrated the influence of epigenetic modifications to immune cell function, highlighting the need for further investigations.

Recent Advances in Hypertension: Epigenetic Mechanism Involved in Development of Salt-Sensitive Hypertension

“…A detailed understanding of epigenetic modulation, including DNA methylation and histone modification, could be promising in targeting certain genes for the prevention and treatment of salt-sensitive hypertension. However, either systemic inhibition of DNMTs by decitabine or intrarenal administration of anti-DNMT3a notably decreased BP in Dahl S rats, 16,17 whereas hypothalamus-specific DNMT3a knockout mice developed salt-sensitive hypertension. 22 This implies that the target genes regulated by DNMT3a are different for the kidney and hypothalamus, resulting in the reciprocal BP response to DNMT3a inhibition.…”

“…Moreover, immunity amplifies the development of salt-sensitive hypertension through aberrant DNA methylation in T cells. 17,51 Because DNA methylation is cell-specific, local or cell-specific administration of epigenetic modifiers, such as DNMT3a inhibitors, is preferred. Furthermore, hypothalamus-specific DNMT3a knockout mice develop obesity in addition to salt-sensitive hypertension, although the target genes for obesity have not been identified.…”

“…16 In addition, inhibition of DNMTs via administration of 5-aza-2ʹ-deoxycystidine (decitabine) blunted salt-induced hypertension and renal damage in Dahl S rats, indicating a functional role of DNA methylation in salt-sensitive hypertension. 17 Interestingly, the maternal diet during the gestation-lactation period has substantial effects on the development of salt-induced hypertension and renal injury in adult Dahl S rats. 18 In humans, moreover, dietary salt restriction induces tissue-specific changes in DNA methylation.…”

Can age be a modifiable risk factor? the impact of dietary patterns on the molecular mechanisms that underlie cardiovascular aging

“…This decrease in MsrA expression leads to decreased homocysteine metabolism to H2S, leading to oxidative stress, vascular inflammation and hypertension [177] . An additional study in mice demonstrated cardiac hypertrophy and differential miRNA expression in cardiac tissue, correlating with percentage of dietary fat and length of HFD exposure [178] .…”

DNA Methylation Sustains “Inflamed” Memory of Peripheral Immune Cells Aggravating Kidney Inflammatory Response in Chronic Kidney Disease

“…In SS rats, a high-salt diet induced increasing global methylation rate in circulating and kidney T cells, of which differentially methylated regions (DMRs) are more prominent in animals with a pronounced hypertensive phenotype. Importantly, the application of decitabine, a hypomethylating agent, significantly attenuates hypertension and renal inflammatory injury in SS rats ( Dasinger et al, 2020 ). In-depth RNA-seq analysis on kidney T cells has revealed the upregulation of multiple inflammatory and oxidative genes in response to a high-salt diet, which are inversely correlated with DNA methylation levels.…”