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. 5 experimental groups; 4 pools/experimental group; 3 rats/pool