Role of Mineralocorticoids in Hypertension

盐皮质激素在高血压中的作用

• 批准号: 8896013
• 负责人: Celso Enrique Gomez-Sanchez
• 金额: $ 28.26万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896013
• 关键词: Acute; Address; Adrenal Cortex; Adrenal Glands; Adrenal Medulla; Adult; Affect; Aldosterone; Aldosterone Synthase; Anabolism; Angiotensin II; Angiotensins; Animal Model; Animals; Area; Axilla; Benign; Bilateral; Blood Pressure; CYP11B2 gene; Ca(2+)-Transporting ATPase; Calcium Channel; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Cholesterol; Chronic; Circadian Rhythms; Corticosterone; Development; Diagnosis; Diet; Diet Modification; Enzymes; Essential Hypertension; Exposure to; Gene Expression Profile; Gene Mutation; Generations; Genes; Gland; Growth; Health; Human; Human Cell Line; Hyperaldosteronism; Hyperplasia; Hypertension; Immunohistochemistry; In Situ; Intake; Kidney; Measurement; Measures; Mediating; Mineralocorticoids; Mitochondria; Modeling; Molecular; Mus; Mutation; Na(+)-K(+)-Exchanging ATPase; Neuropeptide Receptor; Neurotransmitters; Obesity; Obstructive Sleep Apnea; Pathway interactions; Patients; Phenotype; Plasma; Play; Potassium Channel; Production; Rattus; Regulation; Renin; Renin-Angiotensin System; Role; Sampling; Secondary Hypertension; Site; Sodium; Sodium Chloride; Sodium-Restricted Diet; Somatic Mutation; Somatostatin; Specimen; Steroid biosynthesis; Steroids; System; Testing; Tissues; Transcriptional Regulation; Transplantation; Zona Glomerulosa; adenoma; base; capsule; cerebrovascular; human subject; human tissue; laser capture microdissection; low renin hypertension; nerve supply; neuroregulation; receptor; relating to nervous system; steroidogenic acute regulatory protein; tool; transcriptome sequencing; translational approach; tumor

DESCRIPTION (provided by applicant): Primary Aldosteronism (PA) is the most common form of secondary hypertension, affecting 4-14% of those with high blood pressure. PA is associated with a significantly greater increase in cardiovascular and cerebrovascular than patients with essential hypertension with a similar increase and duration of hypertension. Two pathological diagnoses comprise about 98% PA: Idiopathic hyperaldosteronism (IHA) characterized by increased aldosterone synthesis by both adrenals and responsible for 30-70% of PA, and benign aldosterone- producing adenomas (APA). While several gene mutations have been identified in APAs, the cause of IHA is unknown. Neither genetic changes nor changes in known aldosterone (aldo) stimulating factors have been found in IHA patients. We propose to address the following hypothesis: "Idiopathic hyperaldosteronism is in part neurally mediated" and "neural modulation of aldosterone biosynthesis is important and can be explored in surrogate animals." This translational proposal will use human adrenal samples, a human adrenal cortical cell line in culture, and rat models as surrogates to tease out possible mechanisms for IHA. Chronic low sodium maximally stimulates zona glomerulosa growth and aldo synthesis. Acute sodium repletion rapidly suppresses aldo release before the disappearance of rate-limiting enzymes for its synthesis. Specific Aim 1 will characterize the role of adrenal zona glomerulosa innervation from the adrenal medulla and capsule in the regulation of aldosterone secretion and zona glomerulosa remodeling. Rats with intact adrenals, enucleated in situ (medulla and much of the zonas reticularis/fasciculata removed, remaining neural connections to the capsule intact) and enucleated adrenals transplanted into the axilla will be studied after chronic low sodium intake followed by acute voluntary sodium replenishment to distinguish between humoral and neural control. The hypothesis that somatostatin synthesized within the adrenal medulla mediates adrenal suppression upon sodium repletion will be tested. Adrenals of adult humans have clusters of cells that express aldosterone synthase (CYP11B2 enzyme) abundantly amid quiescent ZG cells called aldosterone-producing cell clusters (APCC). Rats on a chronic high salt diet have similar APCC. Exposure to multiple cycles of chronic low sodium intake followed by sodium repletion will be studied to determine if these APCC become larger and/or aldo production becomes autonomous, leading to an IHC phenotype including hypertension in the rats. Transcriptome studies of zona glomerulosa samples of rats on a high sodium diet dissected by laser capture microdissection. Samples rich in clusters of cells expressing high levels of the aldosterone synthase will be compared with quiescent areas. Primary tools will be the measurement of the expression of steroids and genes involved in the control of steroidogenesis, including neurotransmitters know to be present in the adrenal cortex, and immunohistochemistry. We will also study the intrinsic innervation and expression of neuropeptides and receptors, as well as factors discovered in the RNAseq transcriptome studies, in normal human adrenals and those from patients with APA and IHA and correlate our findings from the human subjects with those of the rat models. The aim is to discover how aldosterone synthesis is actively suppressed under normal conditions and whether these mechanisms are defective in IHA and in the adrenal glomerulosa tissues surrounding the adenoma in APA which is often active despite high aldosterone and low renin/angiotensin levels.

描述（由申请人提供）：原发性醛固酮增多症 (PA) 是继发性高血压最常见的形式，影响 4-14% 的高血压患者。与具有相似高血压增加和持续时间的原发性高血压患者相比，PA 与心脑血管增加显着更大相关。约 98% 的 PA 包括两种病理诊断：特发性醛固酮增多症 (IHA)，其特征是双侧肾上腺醛固酮合成增加，占 PA 的 30-70%；以及良性醛固酮生成腺瘤 (APA)。虽然 APA 中已发现多种基因突变，但 IHA 的病因尚不清楚。 IHA 患者中未发现遗传变化或已知醛固酮 (aldo) 刺激因子的变化。我们建议解决以下假设：“特发性醛固酮增多症部分是由神经介导的”和“醛固酮生物合成的神经调节很重要，可以在替代动物中进行探索。”该转化提案将使用人类肾上腺样本、培养的人类肾上腺皮质细胞系和大鼠模型作为替代物来梳理 IHA 的可能机制。慢性低钠最大限度地刺激肾小球带生长和醛醇合成。在其合成的限速酶消失之前，急性钠补充会迅速抑制醛糖的释放。具体目标 1 将描述该角色的特征 肾上腺髓质和囊的肾上腺肾小球带神经支配在醛固酮分泌和肾小球带重塑的调节中的作用。具有完整肾上腺、原位摘除（髓质和大部分网状带/束状带被去除，保留与囊的神经连接完整）和移植到腋窝的摘除肾上腺的大鼠将在长期低钠摄入后进行研究，然后急性自愿补充钠以达到区分体液控制和神经控制。肾上腺髓质内合成的生长抑素在钠补充时介导肾上腺抑制的假设将得到检验。成年人的肾上腺具有大量表达醛固酮合酶（CYP11B2 酶）的细胞簇，这些细胞簇位于静态 ZG 细胞中，称为醛固酮生成细胞簇 (APCC)。长期高盐饮食的大鼠也有类似的 APCC。将研究暴露于慢性低钠摄入随后补充钠的多个周期，以确定这些 APCC 是否变得更大和/或醛酮产生变得自主，从而导致大鼠出现包括高血压的 IHC 表型。通过激光捕获显微切割解剖高钠饮食的大鼠肾小球带样本的转录组研究。富含表达高水平醛固酮合酶的细胞簇的样品将与静止区域进行比较。主要工具将是测量类固醇和参与类固醇生成控制的基因的表达，包括已知存在于肾上腺皮质中的神经递质和免疫组织化学。我们还将研究正常人肾上腺以及 APA 和 IHA 患者的神经肽和受体的内在神经支配和表达，以及 RNAseq 转录组研究中发现的因素，并将我们的人类研究结果与大鼠研究结果相关联模型。目的是发现在正常条件下醛固酮合成如何被主动抑制，以及这些机制在 IHA 和 APA 中腺瘤周围的肾上腺肾小球组织中是否存在缺陷，尽管醛固酮水平较高且肾素/血管紧张素水平较低，但 APA 中腺瘤周围的肾上腺肾小球组织通常很活跃。