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.

近二十年来，醛固酮（Aldo）和盐皮质激素受体（MR）在人体中的作用 疾病已扩展到记录其在各种慢性疾病中的失调 高血压（HTN）：盐摄入量增加会加剧疾病，因此，Aldo/MR 功能障碍。 在我们自由食盐的社会中很常见，并且可能存在于多达 10% 的看似健康的人中 个体和约 16% 患有轻度 HTN 的个体，因此，已开发出针对其中任一种的治疗剂。 阻断 MR 或 Aldo 生物合成的最后一步，实施特定的、个性化的治疗。 治疗 Aldo/MR 介导的常见疾病亚型至少有两种主要方法尚不成熟。 我们的知识差距阻碍了这一目标的实现：1）对 存在自由钠 (Na+) 饮食的情况下 Aldo/MR 失调的机制；2) 生物性别的混杂影响。 为了解决这些差距，我们提出赖氨酸特异性脱甲基酶 1 (LSD1) 是 Aldo/MR 的主要调节因子 LSD1 是一种表观遗传组蛋白修饰酶，在改变盐和性别方面发挥着关键作用。 染色质结构，从而调节转录复合物与 DNA 的接触。LSD1 作用于组蛋白 H3 赖氨酸 4。 (H3K4) 作为转录辅阻遏物或 – 与雌激素/雄激素受体 (ER/AR) 结合 – 在 H3 赖氨酸 9 (H3K9) 作为转录辅激活剂，我们最近报道小鼠体内的 LSD1 水平会降低。 小鼠的饮食盐；LSD1 缺乏（LSD1+/-）与较低的 Aldo 但过度活跃的 MR 相关。 与 Na+ 负载相结合，在 LSD1+/- 小鼠中产生性别二态性：在雄性（但不是雌性）小鼠中衰老 高盐饮食会导致血浆容量、血压和蛋白尿增加，此外，肾小球带 (ZG) 也会增加。 Aldo 生物合成途径中的酶在 LSD1+/- 小鼠中也表现出性别依赖性变化。 这些结果得出了我们的总体假设：LSD1 缺陷是由于其组蛋白 H3K4 的作用改变所致 和 H3K9 位点导致膳食 Na+ 介导的 Aldo 生物合成和 MR 调节出现缺陷 活动，以性别特异性的方式导致心肾损伤，以评估这一假设和结果。 LSD1 和 Aldo/MR 通路之间相互作用的潜在机制，我们将记录 LSD1 作用于 H3K9 调节 Aldo 生物合成途径（目标 1）或作用于 H3K4 调节肾/血管 MR 途径 （目标 2）分别是，目标 3 将确定性激素调节 LSD1 诱导的衰老表型。 有缺陷的小鼠，卵巢激素充当损害的保护者，而睾酮则充当损害的促进者。 实现这些目标将增进我们对 LSD1 介导机制的理解 有了这种机制的了解，临床研究就集中在 ALDO 合成途径的变化上。 具有 LSD1 基因变异的个体将有可能导致基因定义的、性别和饮食特异性的 ALDO 分泌功能失调的预防措施。