Role of Mineralocorticoids in Hypertension

盐皮质激素在高血压中的作用

• 批准号: 7793447
• 负责人: Celso Enrique Gomez-Sanchez
• 金额: $ 25.3万
• 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/7793447
• 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.

说明（申请人提供）：醛固酮在高血压和心血管损伤的发展中起重要作用。原发性醛固酮增多症是一种高血压，其特征是肾上腺皮质球状体自主和过度分泌醛固酮。世界各地的研究表明，原发性高血压的发病率在7-10%之间，难治性高血压患者的发病率更高。控制肾上腺肾小球中醛固酮生物合成的限速酶是CYP 11B 2基因的产物，醛固酮合成酶。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多个基因，有助于表达的转录调节。MicroRNA是一类基因表达的调节因子，最近发现其对胰岛发育、胰岛素分泌、脂肪形成和B细胞发育等至关重要。H295细胞是人肾上腺癌，对醛固酮促分泌素有反应。我们证明了35种不同的microRNA在H295细胞中高度表达，并且最初的微阵列研究表明它们的表达受到醛固酮促分泌素的上调或下调。我们已经研究了mir 21，这些microRNA之一，并发现它是最高表达的大鼠肾上腺的肾小球，并通过与血管紧张素II孵育上调。在H295 R细胞中过表达mir 21可增强血管紧张素II诱导的醛固酮合成，提示mir 21在调节醛固酮生物合成中起作用。我们最近发现了一种新的miRNA，它在大鼠肾小球中表达，来自我们克隆的一种受血管紧张素II高度调控的非编码RNA。我们的假设是：“调节编码醛固酮合成酶的CYP 11B 2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调节肾上腺肾小球细胞增殖和分化，导致肾小球重塑，以响应生理需要，如钠剥夺。提出了以下具体目标来检验这些假设：1。研究在大鼠肾小球功能性微阵列筛选中鉴定的miRNAs的表达，并研究在慢性钠耗竭、血管紧张素II、ACTH输注和肾上腺停用诱导的肾上腺重塑过程中最有希望的候选miRNAs的调节。2.表征参与调节H295 R肾上腺皮质癌细胞系中醛固酮合酶表达和/或醛固酮生物合成的miRNA。公共卫生相关性：醛固酮增多症是继发性高血压最常见的形式，约占全球高血压患者的7-10%。除了增加血压之外，超过生理需要的醛固酮水平，即使是相对温和的，与没有过量醛固酮的类似水平的血压增加相关的心血管、肾脏和脑血管病理学相比，与更大的心血管、肾脏和脑血管病理学相关。治疗仍然局限于盐皮质激素受体拮抗剂。确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。肾上腺皮质的细胞，像许多内分泌和内分泌激素驱动的器官一样，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要。miRNA科学还很年轻。这类翻译调节因子在其他系统中是重要的，这些系统在细胞数量、大小和代谢活性方面自然地经历周期性变化，因此在这些系统的紊乱的病因学中，特别是癌症中是非常重要的，并且对健康护理具有普遍的重要性。 这项建议的一个内在优势在于调查员小组的丰富经验。初步数据进一步加强了所提出的实验，其中包括最近在Endocrinology上发表的一篇文章，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，对研究计划的几个担忧，包括提出要研究的miRNAs的数量，加上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11 b-羟化酶蛋白表达的抗体），以及缺乏解决许多拟议实验局限性的方法，这些都抑制了对应用的热情。