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

在过去的二十年里，醛固酮(ALDO)和盐皮质激素受体(MR)在人类中的作用 疾病已经扩展到在各种慢性病中记录它们的失调，除了 高血压(HTN)。所有人都有共同之处：盐摄入量增加会加剧疾病。因此，Aldo/MR功能障碍 在我们自由的食盐社会中很常见，可能出现在多达10%的表面上健康的人中 轻度HTN的个体和约16%的个体。因此，治疗剂已被开发成 阻断MR或Aldo生物合成的最后一步。然而，实施特定的、个性化的治疗对 Aldo/MR介导的常见疾病亚型的治疗仍不发达。至少有两个主要的 阻碍实现这一目标的知识差距：1)对 在自由钠(Na+)饮食存在的情况下导致Aldo/MR失调的机制；以及2) 生物性行为的混杂效应。 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 带着盐和性的表情。LSD1是一种表观遗传的组蛋白修饰酶，在改变 染色质结构，从而调节转录复合体对DNA的访问。LSD1作用于组蛋白H3赖氨酸4 (H3K4)作为转录共抑制子或-与雌激素/雄激素受体(ER/AR)-在H3 赖氨酸9(H3K9)作为转录共激活剂。我们最近报告说，小鼠体内的LSD1水平降低了 饮食中的盐；小鼠的LSD1缺乏(LSD1+/-)与较低的ALDO但过度活跃的MR有关。 结合Na+负荷在LSD1+/-小鼠中产生性二型性：在雄性(但不是雌性)小鼠中 高盐饮食导致血浆容量、血压和蛋白尿增加。此外，球状带(ZG) Aldo生物合成途径中的酶在LSD1+/-小鼠中也显示出性别依赖性的变化。 这些结果导致了我们的总体假设：LSD1缺乏症是通过改变组蛋白H3K4的作用来实现的 和H3K9位点导致膳食Na+介导的Aldo生物合成和MR调节的缺陷 活动，导致特定性别的心肾损害。为了评估这一假设和 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以调节Aldo生物合成途径(目标1)或作用于H3K4以调节肾脏/血管MR途径 (目标2)。目标3将确定性激素调节LSD1衰老诱导的表型 缺乏卵巢的小鼠，卵巢激素起到保护作用，而睾丸激素起到促进损伤的作用。 实现这些目标将促进我们对LSD1介导的潜在机制的理解 Aldo合成途径的变化。有了这种机械性的理解，集中的临床研究 携带LSD1基因变异的个体可能导致基因定义的、性别和饮食特定的 Aldo分泌功能障碍的预防措施。

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.