OR04-3 Lysine-Specific Demethylase-1 (LSD1) Deficiency Increases Aldosterone Signaling via Mineralocorticoid Receptor Activation

Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation of gene transcription. We have shown that human risk allele carriers of a LSD1 variant as well as a LSD1 heterozygous knockout mice (LSD1+/-) have salt sensitive hypertension (HTN), but low aldosterone (ALDO) and plasma renin activity (PRA) levels. However, in young mice ALDO levels are inappropriately increased for the level of salt intake. Thus, we hypothesize that despite the low ALDO levels, the salt sensitive HTN is mineralocorticoid mediated secondary to an overactive mineralocorticoid receptor(MR). To test our hypothesis, wild-type (LSD1+/+) and LSD1+/- mice were fed a liberal sodium (1.6% Na+) diet for 7 days and were then randomized to placebo or eplerenone (Epl) treatment for 2 weeks. Systolic blood pressures (SBP) were measured before and after the intervention; albumin/creatinine ratios (A/C), plasma ALDO, as well as urine ALDO, sodium and potassium were measured at the end of the study. Results: Compared with LSD1+/+, LSD1+/- mice displayed higher SBP at the beginning of the study (132 ± 2.6 mmHg vs 113.8 ± 2.0 mmHg; P