Abstract Body: Hypertension is caused by a combination of genetic and environmental factors. Angiotensinogen (AGT) is a component of RAAS, that regulates blood pressure. GWAS have shown that two A/G polymorphisms (rs2493134 and rs2004776), located at +507 and +1164 in intron I of the human AGT (hAGT) gene, are linked to hypertension. AGT gene polymorphisms result in two main haplotypes. Hap-I contains the variants -217A, -6A, +507G, and +1164A and is pro-hypertensive, whereas Hap-II contains the variants -217G, -6G, +507A, and +1164G and is normotensive. Increasing scientific evidence supports high salt's effect on blood pressure regulation. In this study, we have investigated the impact of high salt on the epigenetic and transcriptional regulation of the hAGT gene in Hap-I and Hap-II transgenic mice. We treated twelve-week TG mice with a 4% high salt diet (HSD) and identified DNA methylation patterns by bisulfite kit. RT-PCR and immunoblot analyses show that hAGT gene expression is increased by HSD in Hap-I and Hap-II TG mice. In the liver and kidney tissues of Hap-I TG mice, HSD significantly reduced the number of CpG sites in the hAGT promoter. These results suggest that HSD promotes DNA demethylation and increases AGT gene expression. Chip assay has shown that transcription factors USF1, STAT3, HNF1a, C/EBP-β, and GR bind strongly after HSD treatment. RNA-Seq identified differentially expressed genes, novel target genes associated with hypertension, top canonical pathways, and upstream regulators. Combining epigenetic and transcriptional analysis allows for a more holistic understanding of the regulatory mechanisms that govern the hAGT gene.