Role of Mineralocorticoids in Hypertension

盐皮质激素在高血压中的作用

• 批准号: 7656988
• 负责人: Celso Enrique Gomez-Sanchez
• 金额: $ 30.3万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656988
• 关键词: Accounting; Address; Adrenal Cortex; Adrenal Gland Adenoma; Adrenal Gland Carcinoma; Adrenal Glands; Adrenocortical carcinoma; Aldosterone; Aldosterone Synthase; Anabolism; Angiotensin II; Animals; Antibodies; Apoptosis; B-Cell Development; Benign; Blood Pressure; CYP11B1 gene; CYP11B2 gene; Cardiovascular system; Cell Count; Cell Line; Cell Proliferation; Cells; Chronic; Corticosterone; Corticotropin; Coupled; Data; Defect; Deoxycorticosterone; Development; Diet; Disease; Endocrine; Endocrinology; Enzymes; Essential Hypertension; Etiology; Functional RNA; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Germ Cells; Glucocorticoids; Healthcare; Hormones; Human; Hyperaldosteronism; Hypertension; Incidence; Infusion procedures; Investigation; Islets of Langerhans; Kidney; Left Ventricular Hypertrophy; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; MicroRNAs; Mineralocorticoid Receptor; Mineralocorticoids; Mixed Function Oxygenases; Morbidity - disease rate; Mus; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Physiological; Physiological Processes; Play; Population; Potassium Channel; Production; Proliferating; Proteins; Publications; Rattus; Reagent; Refractory; Regulation; Regulator Genes; Research; Research Personnel; Risk Factors; Role; Sampling; Science; Secondary Hypertension; Small Interfering RNA; Small RNA; Sodium; Stem cells; Steroids; Stimulus; System; Technology; Testing; Transcriptional Regulation; Transfection; Translating; Translational Regulation; Translations; Undifferentiated; Virus; Zona Fasciculata; Zona Glomerulosa; adenoma; cell determination; cerebrovascular; deprivation; endocrine pancreas development; experience; feeding; human tissue; insight; insulin secretion; interest; lipid biosynthesis; mineralocorticoid hypertension; mortality; novel; overexpression; promoter; protein expression; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): Aldosterone plays a significant role in the development of hypertension and cardiovascular damage. Primary aldosteronism is a form of hypertension characterized by the autonomous and excessive secretion of aldosterone by the adrenal zona glomerulosa. Studies throughout the world have shown that the incidence is between 7-10% of essential hypertensives, and higher in patients with refractory hypertension. The rate limiting enzyme in the control of aldosterone biosynthesis in the zona glomerulosa of the adrenal is the product of the CYP11B2 gene, aldosterone synthase. Aldosterone synthase is regulated at the transcriptional level and we and others have described multiple genes that contribute to the transcriptional regulation of the expression. MicroRNAs are a class of regulators of gene expression that have recently been found to be crucial for pancreatic islet development, insulin secretion, adipogenesis, and B-cell development, and others. The H295 cell is a human adrenal carcinoma and responds to aldosterone secretagogues. We demonstrated that 35 different microRNAs are highly expressed in H295 cells and initial microarray studies suggest that their expression is up or down regulated by aldosterone secretagogues. We have studied mir21, one of these microRNAs, and found that it is most highly expressed in the zona glomerulosa of the rat adrenal and is upregulated by incubation with angiotensin II. Overexpression of mir21 in H295R cells enhances aldosterone synthesis in response to angiotensin II, suggesting that mir21 plays a role in the regulation of aldosterone biosynthesis. We have recently discovered a new miRNA that is expressed in the rat zona glomerulosa from a non-coding RNA that we cloned that is highly regulated by angiotensin II. Our hypotheses are: "Genes that regulate the transcription and translation of the CYP11B2 gene encoding Aldosterone Synthase and directly or indirectly modulate aldosterone biosynthesis are regulated by adrenal glomerulosa-specific MicroRNAs." In addition, "MicroRNAs regulate adrenal zona glomerulosa cellular proliferation and differentiation resulting in zona glomerulosa remodeling" in response to physiological need, such as sodium deprivation. The following specific aims are proposed to test these hypotheses: 1. Study the expression of miRNAs identified in functional microarray screens of rat zona glomerulosa and study the regulation of the most promising candidate miRNAs during adrenal remodeling induced by chronic sodium depletion, angiotensin II, ACTH infusion, and adrenal decommissioning. 2. Characterize the miRNAs that participate in the regulation of the expression of the aldosterone synthase and/or aldosterone biosynthesis in the H295R adrenal cortical carcinoma cell line. PUBLIC HEALTH RELEVANCE: Aldosteronism is the most common form of secondary hypertension, accounting for about 7-10% of unselected patients with hypertension World-wide. In addition to increasing blood pressure, levels of aldosterone in excess of physiological need, even when relatively mild, are associated with a greater cardiovascular, renal and cerebrovascular pathology than that associated with similar levels of blood pressure increase without excessive aldosterone. Treatment remains limited to mineralocorticoid receptor antagonists. Identifying genes involved in adrenal remodeling and aldosterone production will allow us to address the pathogenesis of Idiopathic Hyperaldosteronism directly. Cells of the adrenal cortex, like many endocrine and endocrine hormone-driven organs, must proliferate, regulate hormone synthesis and undergo apoptosis in response to ever-changing physiological circumstances and need. The science of miRNAs is still very young. The potential that this class of translational regulators are important in other systems that naturally undergo cyclic changes in cell number, size and metabolic activity, and thus in the etiology of derangements of these, particularly cancer, is very great and of general importance to health care. An inherent strength of the proposal lies in the extensive experience of the team of investigators. The experiments proposed are further strengthened by preliminary data, which include a recent publication in Endocrinology, that provide compelling evidence for miRNA-dependent modulation of aldosterone secretion. However, several concerns about the research plan, including the number of miRNAs proposed to be investigated coupled with the lack of a detailed strategy of how efforts will be focused, the lack of key reagents (antibodies to assess aldosterone synthase and 11b-hydroxylase protein expression), and the absence of approaches to address the limitations of many of the proposed experiments temper enthusiasm for the application.

描述（由申请人提供）：醛固酮在高血压和心血管损伤的发生中起着重要作用。原发性醛固酮增多症是一种高血压，其特征是肾上腺肾小球带自主过量分泌醛固酮。世界各地的研究表明，原发性高血压的发病率为7-10%，难治性高血压患者的发病率更高。控制肾上腺球状带醛固酮生物合成的限速酶是 CYP11B2 基因醛固酮合酶的产物。醛固酮合酶在转录水平上受到调节，我们和其他人已经描述了有助于表达的转录调节的多个基因。 MicroRNA 是一类基因表达调节因子，最近发现它们对于胰岛发育、胰岛素分泌、脂肪生成和 B 细胞发育等至关重要。 H295 细胞是一种人类肾上腺癌，对醛固酮促分泌剂有反应。我们证明了 35 种不同的 microRNA 在 H295 细胞中高表达，最初的微阵列研究表明它们的表达受到醛固酮促分泌剂的上调或下调。我们研究了 mir21（其中一种 microRNA），发现它在大鼠肾上腺的肾小球带中表达最高，并且通过与血管紧张素 II 一起孵育而上调。 H295R 细胞中 mir21 的过度表达会增强血管紧张素 II 的醛固酮合成，表明 mir21 在醛固酮生物合成的调节中发挥作用。我们最近发现了一种新的 miRNA，它在大鼠肾小球带中表达，来自我们克隆的非编码 RNA，该 RNA 受到血管紧张素 II 的高度调节。我们的假设是：“调节编码醛固酮合酶的 CYP11B2 基因的转录和翻译并直接或间接调节醛固酮生物合成的基因受到肾上腺肾小球特异性 MicroRNA 的调节。”此外，“MicroRNA 调节肾上腺肾小球带细胞增殖和分化，导致肾小球带重塑”，以响应生理需求，例如缺钠。提出以下具体目标来检验这些假设： 1. 研究大鼠球状带功能微阵列筛选中鉴定的 miRNA 的表达，并研究最有希望的候选 miRNA 在慢性缺钠、血管紧张素 II、ACTH 诱导的肾上腺重塑过程中的调节输注和肾上腺停用。 2. 表征参与 H295R 肾上腺皮质癌细胞系中醛固酮合酶表达和/或醛固酮生物合成调节的 miRNA。公众健康相关性：醛固酮增多症是继发性高血压最常见的形式，约占全世界未经选择的高血压患者的 7-10%。除了血压升高之外，醛固酮水平超过生理需要，即使相对轻微，也会与心血管、肾和脑血管病理学相关，而醛固酮水平相似的血压升高则与没有过量醛固酮的情况相比，会导致更严重的心血管、肾和脑血管病变。治疗仍然仅限于盐皮质激素受体拮抗剂。鉴定参与肾上腺重塑和醛固酮生成的基因将使我们能够直接解决特发性醛固酮增多症的发病机制。与许多内分泌和内分泌激素驱动的器官一样，肾上腺皮质细胞必须增殖、调节激素合成并经历细胞凋亡，以响应不断变化的生理环境和需求。 miRNA 科学还很年轻。这类翻译调节因子在细胞数量、大小和代谢活性自然经历周期性变化的其他系统中非常重要，因此在这些系统（特别是癌症）紊乱的病因学中具有非常重要的潜力，并且对医疗保健具有普遍重要性。 该提案的内在优势在于研究团队的丰富经验。初步数据进一步强化了拟议的实验，其中包括最近发表在《内分泌学》上的一篇文章，为醛固酮分泌的 miRNA 依赖性调节提供了令人信服的证据。然而，对该研究计划的一些担忧，包括提议研究的 miRNA 数量，以及缺乏如何集中精力的详细策略、缺乏关键试剂（评估醛固酮合酶和 11b-羟化酶蛋白表达的抗体） ），并且缺乏解决许多拟议实验的局限性的方法，削弱了应用的热情。