Abstract 097: Effects of Lysine-specific Demethylase 1 Deficiency on Aldosterone Production and Salt-sensitive Hypertension in Female Mice

Abstract

Lysine-Specific Demethylase1 (LSD1) is an epigenetic factor modulated by salt intake. Previously, we documented the male heterozygote LSD1 knockout mice (LSD1+/-) had dysregulation of aldosterone (ALDO) production on a liberal salt diet (1.6% Na+) associated with salt-sensitive hypertension. This study assessed if: 1) female LSD1+/- mice have a similar phenotype; and 2) the effect of aging on this phenotype. Methods: Female LSD1+/- and wild type mice (LSD1+/+) were randomly assigned for sacrifice at the ages of 18-week, 52-week, and 75-week and the following were assessed at each time point: blood pressure (BP); plasma renin activity (PRA) and ALDO; urine albumin; and ex vivo ALDO production from isolated adrenal zona glomerulosa cells. Results: BP and urine albumin in the LSD1+/- compared to the LSD1+/+ were not different at any age (Table). However, the LSD1+/- had greater ALDO/PRA ratios at 18 weeks compared with the LSD1+/+, but lower ALDO levels and ex vivo ALDO production at 52 and 75 weeks. Associated with this phenotype, the LSD1+/- showed significantly higher rate of all-cause mortality than the LSD1+/+. Conclusion: Lack of LSD1 caused dysregulation of ALDO production in both male and female mice. But the cardiovascular outcomes are different. The LSD1+/- females in contrast to males do not develop hypertension or albuminuria even at 75 weeks of age. However, the females do die at a faster rate than the males of a variety of causes. Thus, there is considerable sexual dimorphism in the pathogenesis of cardiovascular outcomes associated with dysregulation of adrenal ALDO production mediated by lack of LSD1.