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）的作用 疾病已经扩展到记录其在多种慢性疾病中的失调 高血压（HTN）。所有人共同：增加的盐摄入量加剧了这种疾病。那是阿尔多/功能障碍先生 在我们消耗盐的社会中很常见，可能有多达10％的健康状况 个体和约16％的轻度HTN个体。那是开发出治疗剂的 阻止Aldo生物合成的MR或最后一步。但是，实施特定的个性化疗法 治疗常见疾病的Aldo/MR介导的亚型仍未发育。至少有两个专业 在我们的知识中差距阻碍了实现这一目标的实现：1）对 在存在自由钠（Na+）饮食的情况下，在Aldo/MR失调下的机制； 2） 生物学性别的混杂作用。 为了解决这些差距，我们建议赖氨酸特异性去甲基酶1（LSD1）是Aldo/MR的主要调节剂 用盐和性表达。 LSD1是一种表观遗传学，修饰酶，在改变方面起着至关重要的作用 染色质结构，因此调节转录复合物对DNA的访问。 LSD1作用于组蛋白H3赖氨酸4 （H3K4）作为转录共抑制剂或与雌激素/雄激素受体（ER/AR）一起使用H3 赖氨酸9（H3K9）作为转录共激活因子。我们最近报告说，小鼠的LSD1水平降低了 饮食盐；小鼠中的LSD1缺乏症（LSD1 +/-）与较低的Aldo相关但过度活跃的MR。此外，衰老 与Na+载荷的联系会在LSD1 +/-小鼠中产生性二态性：在雄性（但不是雌性）小鼠衰老的小鼠中 高盐饮食会引起血浆体积，BP和蛋白尿的增加。此外，Zona glomerulosa（ZG） Aldo生物合成途径中的酶还显示了LSD1 +/-小鼠的性别依赖性变化。 这些结果导致了我们的总体假设：LSD1缺乏通过其组蛋白H3K4的改变的作用而变化 和H3K9位点在饮食中的Na+介导的Aldo生物合成和MR的调节中导致缺陷 活动，以特定性别的方式导致心脏卫生损害。评估这一假设和 LSD1与Aldo/MR Pathways之间相互作用的机制，我们将记录LSD1 作用于H3K9来调节Aldo Biosynthetic途径（AIM 1）或在H3K4上进行肾脏/血管MR途径 （AIM 2）分别。 AIM 3将确定性恐怖调节LSD1中衰老引起的表型 缺乏小鼠，卵巢骑兵充当防护子，睾丸激素作为损伤的启动子。 实现这些目标将提高我们对LSD1介导的机制的理解 Aldo合成途径的变化。有了这种机械理解，专注于 具有LSD1基因变异的个体可能会导致遗传定义，性别和饮食特异性 功能失调的ALDO分泌的预防测量。