Salt-sensitive hypertension and renal damage were compared in colonies of SS rats fed casein-and grain-based diets. When 6 week old rats were fed a low NaCl diet (n=7-11/group), mean arterial pressure (MAP) and urinary albumin (UAlb) excretion were not significantly different in grain-fed rats compared to values in casein-fed rats (107±2 mmHg and 6±2 mg/day). Increasing dietary NaCl intake to 4.0% for three weeks led to a significantly greater increase in MAP (171±7 vs 119±7 mmHg), UAlb (164±19 vs 24±6 mg/day) and renal histological damage in SS rats fed the casein diet (p<.05). To assess mechanisms of this NaCl independent effect, an RNA-Seq analysis of renal outer medullary tissue of rats (n=4/group) fed the grain- or casein-based diets was performed. Over 1500 known genes were differentially expressed between the casein- and grain-fed rats on low salt; over 2100 were different between the groups fed the 4.0% chow (FDR<0.05); and 897 genes were common to these two data sets. The differentially expressed genes were significantly enriched for genes related to hematopoietic cell lineage, the complement and coagulation cascade, B-cell signaling, NK cell-mediated cytotoxicity, and primary immunodeficiency. To understand potential mechanisms of the regulation of gene expression, a genome-wide DNA methylation analysis of the renal outer medulla at single-base resolution was performed. Of nearly 3,000 methylated CpG islands identified, 534 and 650 were differentially methylated between the casein and grain fed groups when comparing effects of low to high salt diets, respectively (FDR<0.05). Approximately 200 differentially methylated CpG islands were located in the proximity of transcriptional start sites. We first focused our attention on several genes which exhibited a reciprocal pattern of DNA methylation and RNA abundance. These include Klotho (an aging-related gene), and Cyp39a1 (a cytochrome P450) which exhibited significantly more 5-methylcytosine modifications in the transcription start site and reduced mRNA expression in rats fed the casein-based diet with low salt. These data provide evidence that epigenetic modifications due to NaCl-independent dietary effects may alter salt-sensitive blood pressure and renal disease phenotypes.