Dietary Effects on T Cell Methylomes and Functional Inhibition of DNA Methyltransferase Attenuates Salt-Sensitive Hypertension and Renal Damage in Dahl SS Rat

The Dahl salt-sensitive (SS) rat is an established model of hypertension and renal damage that is accompanied with an activation of the immune system in the 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 Dahl SS/JrHsdMcwi (SS/MCW) rats maintained on a purified diet (AIN-76A) presenting with a more severe phenotype relative to the grain-fed Dahl SS/JrHsdMcwiCrl rat (SS/CRL). Recently, T cells isolated from the kidneys of the two strains unveiled that transcriptomic and functional differences may contribute to the susceptibility of hypertension and renal damage. 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 strains. In response to high salt challenge, the methylome of T cells isolated from the kidney of SS/MCW exhibit significantly more differentially methylated regions with a preference for hypermethylation compared to the SS/CRL kidney T cells. Circulating T cells exhibited similar methylation profiles between the strains. 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. The study demonstrated the influence of epigenetic modifications to immune cell function, highlighting the need for further investigations.Dahl盐敏感性大鼠（Dahl salt-sensitive, SS）是已确立的高血压与肾损伤实验模型，该模型在高盐饮食刺激下会伴随免疫系统激活。针对饮食中钠非依赖性与钠依赖性成分的研究表明，其可影响疾病表型：喂食纯化饲料（AIN-76A）的Dahl SS/JrHsdMcwi（SS/MCW）大鼠，相比喂食谷物饲料的Dahl SS/JrHsdMcwiCrl（SS/CRL）大鼠，疾病表型更为严重。近期，从这两个品系大鼠肾脏中分离的T细胞研究揭示，转录组与功能差异可能是高血压及肾损伤易感性的成因之一。鉴于已有研究证实免疫系统、环境与饮食可改变该表型，本研究对这两个品系大鼠外周血及肾脏中分离的T细胞的表观遗传谱进行了分析。在高盐刺激下，与SS/CRL大鼠肾脏T细胞相比，SS/MCW大鼠肾脏T细胞的甲基化组中存在更多显著差异甲基化区域，且更倾向于高甲基化。两个品系的循环T细胞甲基化谱较为相似。利用对同一批实验动物T细胞进行转录组分析与DNA甲基化分析所得的数据，本研究在所有组别中均观察到基因表达与DNA甲基化之间存在显著负相关关系。最后，DNA甲基转移酶抑制剂可减弱SS/MCW大鼠盐诱导的高血压与肾损伤，证实了甲基化的功能性作用。本研究揭示了表观遗传修饰对免疫细胞功能的影响，凸显了后续深入研究的必要性。