Epigenetic Modification of Immune Mechanisms in Salt-Sensitive Hypertension and Renal Damage

Experiments in animals and human data indicate that the immune system is important in the development of hypertension and kidney damage and provides a link between the environment and disease. In this proposal, we present preliminary data, obtained with embryo transfer techniques, demonstrating that sodium-independent changes in the diet, mediated in the maternal environment, can profoundly attenuate sodium-sensitive hypertension and renal disease phenotypes in adult offspring of Dahl Salt Sensitive (SS) rats. A subsequent genome-scale methylation analysis demonstrated significant differences in methylation of circulating T lymphocytes and renal outer medullary tissue in rats from mothers fed different diets. Further studies demonstrated that selective knockdown of DNMT3A, an enzyme that catalyzes de novo methylation of DNA, amplified hypertension in SS rats. These novel data indicate that epigenetic alterations in immune cells, resulting from an altered maternal environment, can profoundly impact salt-sensitive hypertension and renal damage. The present studies are designed to examine the importance of DNA methylation in immune cells in the progression of disease in SS rats. This project will test the general hypothesis that the maternal dietary environment alters the epigenomic program in immune cells in SS rats and their de novo methylation response to an increased salt intake in adult life, which in turn affects immune cell infiltration and activation in the kidney and modifies salt-sensitive hypertension and renal disease. This hypothesis will be tested in three integrated aims. Aim 1 will test the hypothesis that the maternal environment alters DNA methylation, RNA expression, immune cell phenotypes, and disease phenotypes in adult SS rats. Aim 2 will test the hypothesis that the hematopoietic cell compartment plays a role in the determination of the SS disease phenotype, which is associated with epigenomic modifications in these cells. Aim 3 will test the hypothesis that de novo DNA methylation causally contributes to SS hypertension and renal damage. This hypothesis may provide an important link between the environment and disease and help explain the 'missing heritability' in hypertension. These integrative aims will utilize unique experimental approaches including novel genetically-manipulated animal models, embryo transfer experiments, base-resolution mapping of DNA methylation, RNA-Seq, and bone-marrow transfer studies. (AHA Program: Strategically Focused Research Network)