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（PA）是次要高血压的最常见形式，影响高血压的人中有4-14％。 PA与具有高血压的基本高血压患者相比，心血管和脑血管脑血管的增长明显更大，高血压的增加和持续时间。两种病理诊断约为98％PA：特发性大甲醛酸（IHA）（IHA），其特征是肾上腺的醛固酮合成增加，负责30-70％的PA和良性醛固酮产生腺苷（APA）。尽管在APA中已经鉴定出了几个基因突变，但IHA的原因尚不清楚。 IHA患者均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：“特发性高醛源性部分是神经介导的”和“醛固酮生物合成的神经调节很重要，可以在替代动物中探索。”该翻译建议将使用人类肾上腺样本，培养中人类肾上腺皮质细胞系，而大鼠模型则作为替代品，以取消IHA的可能机制。慢性低钠最大刺激Zona肾小球生长和Aldo合成。急性钠的补充会在限制酶的合成之前迅速抑制Aldo释放。特定目标1将表征角色 在醛固酮分泌和Zona glomerulosa重塑的调节中，从肾上腺髓质和胶囊肾上腺肾小球神经支配进行。具有完整肾上腺的大鼠，塞核的原位（髓质和大部分叶片网状/fasciculata被移除，剩余的神经连接到胶囊完整），并在慢性低硫化含量后，将在慢性低硫化后进行良好的自发性控制后，将被移植到腋窝中的in核肾上腺。将测试肾上腺髓质中合成的生长抑素合成的假说将测试钠的肾上腺抑制。成年人类的肾上腺具有表达醛固酮合酶（CYP11B2酶）的细胞簇，在称为产生醛固酮的细胞簇（APCC）的静止的ZG细胞中。慢性高盐饮食的大鼠具有相似的APCC。将研究暴露于多个慢性低钠摄入量的循环，然后研究钠含量，以确定这些APCC是否变得更大，并且/或Aldo产生自治，从而导致IHC表型，包括大鼠的高血压。通过激光捕获显微解剖解剖的高钠饮食中大鼠zona肾小球样品的转录组研究。将富含表达高水平醛固酮合酶的细胞簇的样品与静态区域进行比较。主要工具将是测量与控制类固醇生成的类固醇和基因的表达，包括神经递质已知存在于肾上腺皮质中，以及免疫组织化学。我们还将研究神经肽和受体的固有神经和表达，以及在正常人类肾上腺中的RNASEQ转录组研究中发现的因素，以及来自APA和IHA患者的肾上有神经支配和表达，并将人类受试者的发现与大鼠模型相关。目的是发现醛固酮合成如何在正常条件下积极抑制，以及这些机制在IHA和APA腺瘤周围的肾上腺肾小球组织中是否有缺陷，APA中的肾上腺肾小球组织是否经常活跃，尽管醛固酮高和肾素较低/血管素/血管紧张素水平。