Aldosterone/mineralocorticoid receptor responses to biologic sex and salt intake: Role of Lysine Specific Demethylase 1 (LSD1)

点击翻译按钮获取中文摘要

In the past two decades, the roles of aldosterone (Aldo) and the mineralocorticoid receptor (MR) in human disease have expanded to documenting their dysregulation in a variety of chronic diseases in addition to hypertension (HTN). Common to all: increased salt intake exacerbates the disease. Thus, Aldo/MR dysfunction is common in our liberal salt-consuming society and may be present in as many as 10% of apparently healthy individuals and ~ 16% of individuals with mild HTN. Thus, therapeutic agents have been developed to either block the MR or the last step in Aldo biosynthesis. However, implementation of specific, personalized therapy to treat Aldo/MR mediated subtypes of common diseases is still underdeveloped. There are at least two major gaps in our knowledge that are preventing the achievement of this goal: 1) limited understanding of the mechanisms that underly the Aldo/MR dysregulation in the presence of a liberal sodium (Na+) diet; and 2) the confounding effects of biologic sex. To address these gaps, we propose that Lysine Specific Demethylase 1 (LSD1) is a major regulator of Aldo/MR expression with salt and sex. LSD1 is an epigenetic, histone-modifying enzyme and plays a critical role in altering chromatin structure, thus modulating transcription complexes access to DNA. LSD1 acts on histone H3 lysine 4 (H3K4) as a transcription co-repressor or – in conjunction with estrogen/androgen receptors (ER/AR) – at H3 lysine 9 (H3K9) as a transcription co-activator. We recently reported that LSD1 levels in mice are decreased by dietary salt; LSD1 deficiency (LSD1+/-) in mice associates with lower Aldo but overactive MR. Further, aging in conjunction with Na+ loading yields a sexual dimorphism in LSD1+/- mice: in male (but not female) mice aging on a high salt diet induces increases in plasma volume, BP and albuminuria. In addition, Zona Glomerulosa (ZG) enzymes in the Aldo biosynthetic pathway also display sex-dependent changes in LSD1+/- mice. These results have led to our overall hypothesis: LSD1 deficiency via its altered actions of histone H3K4 and H3K9 sites causes defects in the dietary Na+ mediated regulation of Aldo biosynthesis and MR activity, leading to cardio-renal damage in a sex-specific fashion. To assess this hypothesis and the mechanisms underlying the interactions between LSD1 and Aldo/MR pathways, we will document that LSD1 acts at H3K9 to modulate the Aldo biosynthetic pathway (Aim 1) or at H3K4 for the renal/vascular MR pathway (Aim 2), respectively. Aim 3 will establish that sex hormones modulate the aging-induced phenotype in LSD1 deficient mice, with ovarian hormones acting as protectors against, and testosterone as a promotor of damage. Accomplishing these objectives will advance our understanding of the LSD1-mediated mechanisms underlying the changes in the ALDO synthesis pathway. With this mechanistic understanding, focused clinical studies in individuals with LSD1 gene variants will be possible leading to genetically defined, sex- and diet-specific preventive measures for dysfunctional ALDO secretion.