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

Abstract

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<0.001). As compared to placebo, treatment with eplerenone significantly reduced SBP in LSD1+/- but not LSD1+/+ mice (LSD1+/-+ epl: 120.8 ± 1.6 mmHg vs LSD1+/- + placebo 134.1± 4.3 , P = 0.02). LSD1+/- mice also displayed significantly higher A/C ratios than the LSD1+/+ (68.0 ± 23.6 µg/mg vs 22.1 ± 1.6 µg/mg, P = 0.04), and treatment with eplerenone reduced A/C in LSD1+/- mice to levels indistinguishable from those in the LSD1+/+ (LSD1+/- + epl. 27.3 ± 2.9 µg/mg vs LSD1+/+ + epl 26.0 ± 1.7 µg/mg). Urine ALDO/creatinine ratios were significantly lower in LSD1+/- vs. LSD1+/+ (26.1 ± 4.0 pg/mg vs 39.4 ± 4.1 pg/mg ,P = 0.03). Plasma ALDO showed a similar trend for lower levels in LSD1+/- vs. LSD1+/+ (21.8 ± 5.1 ng/dl vs 33.5 ± 6.1 ng/dl). In contrast, LSD1+/- had significantly higher 24-hr urine potassium than the LSD1+/+ mice (0.29 ± 0.1 mmol vs 0.15 ± 0.02 mmol, P= 0.05), yet similar ALDO responses to eplerenone, suggesting increased MR activity. Conclusion: Our data support our hypothesis that inappropriately activated MR signaling mediates the cardio-renal defects in the LSD1 deficient mouse. These findings support the concept that treatment with an MR antagonist may result in improved cardio- and reno-vascular outcomes in human LSD1+/- risk allele carriers.