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

醛固酮/盐皮质激素受体对生物性别和盐摄入量的反应：赖氨酸特异性脱甲基酶 1 (LSD1) 的作用

• 批准号: 10930190
• 负责人: Luminita Pojoga
• 金额: $ 83.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10930190
• 关键词: Achievement; Address; Adrenal Glands; Adverse effects; African ancestry; Aging; Albuminuria; Aldosterone; Anabolism; Androgen Receptor; Blood Plasma Volume; Blood Vessels; Cells; Chromatin Structure; Chronic Disease; Clinical Research; Complex; Consumption; DNA; Defect; Development; Diet; Dietary Sodium; Disease; Endothelial Cells; Enhancers; Enzymes; Epigenetic Process; Estrogen Receptor alpha; Estrogens; Female; Functional disorder; Gene Activation; Genes; Genetic; Genetic Transcription; Goals; Gonadal Steroid Hormones; Histone H3; Histones; Human; Hypertension; Individual; KDM1A gene; Kidney; Knowledge; Lysine; Mediating; Microalbuminuria; Mineralocorticoid Receptor; Mus; Orchiectomy; Outcome; Ovarian hormone; Ovary; Pathway interactions; Phenotype; Play; Preventive measure; Proteins; Receptor Activation; Regulation; Reporting; Role; Signal Pathway; Site; Societies; Sodium; Sodium Chloride; Stress; Testis; Testosterone; Therapeutic Agents; Tissues; Transcription Coactivator; Transcriptional Activation; Variant; Zona Glomerulosa; age related; biological sex; dietary; dietary salt; gene repression; genetic corepressor; genetic variant; high salt diet; human disease; in vivo; kidney cell; male; personalized medicine; prevent; promoter; receptor; receptor expression; response; salt intake; sex; sexual dimorphism

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.

在过去的二十年中，醛固酮（Aldo）和矿物皮质激素受体（MR）在人体中的作用