Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension

Abstract

Background: Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).

Methods: Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1(+/-)) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American).

Results: LSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1(+/-) mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1(+/-) mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1(+/-) mice, decreased α-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.

Conclusion: The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.

Figure 1. Effect of dietary sodium on LSD-1 protein levels in mouse kidney

^# LSD-1 protein levels were significantly higher on low salt (LS) compared to liberal salt (HS) diet in kidney tissue of wild-type (WT) mice (N=3–4; p < 0.01). * In LSD-1 heterozygote knockout (LSD-1+/−) mice, LSD-1 protein levels in the kidney were significantly lower compared to WT mice on both diets (N=3–4; p < 0.05). LSD-1 protein levels in the LSD-1+/− mice did not change significantly between diets. Error bars = SEM.

Figure 2. Effect of LSD-1 genetic variants on the systolic blood pressure (SBP) response to dietary salt in African-American Hypertensive Subjects

^# African-American hypertensive minor allele carriers of LSD-1 rs587168 (N=26) compared with major allele homozygotes (N=28) had significantly greater increase in SBP in response to change from low salt to liberal salt diet (p < 0.01). Data shown are mean values adjusted for age, gender and BMI differences. Error bars = SEM. A significant association of the minor allele with salt-sensitivity of BP was also seen for rs671357 (data not shown; p = 0.01) in the African-American cohort.

Figure 3. ENaC expression on liberal salt diet

^# LSD-1 heterozygote knockout (LSD-1+/−) compared with wild-type (WT) mice, had significantly lower expression of the alpha subunit of renal epithelial sodium channel (ENaC) (N=3–4 mice in each group; p < 0.01) on liberal salt diet. Error bars=SEM.

Figure 4. Aldosterone levels by LSD1 genotype

^# African-American hypertensive minor allele carriers of rs587168 (N=26) had significantly lower serum aldosterone levels compared with major allele homozygotes (N=28) on liberal salt diet (p <0.01). Error bars = 95% confidence interval.