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展中起着重要作用。原发性醛固酮主义是一种高血压形式，其特征是肾上腺Zona glomerulosa对醛固酮的自主和过度分泌。全世界的研究表明，发病率是基本高血压的7-10％，而难治性高血压患者的发病率更高。肾上腺Zona肾小球中醛固酮生物合成控制中的速率限制酶是CYP11B2基因，醛固酮合酶的乘积。醛固酮合酶受到转录水平的调节，我们和其他人描述了有助于表达的转录调节的多个基因。 microRNA是一类基因表达的调节剂，最近发现对胰岛发育，胰岛素分泌，脂肪生成和B细胞发育等至关重要。 H295细胞是人类的肾上腺癌，对醛固酮促分子作出反应。我们证明了35种不同的microRNA在H295细胞中高度表达，初始微阵列研究表明它们的表达是由醛固酮促分泌物调节的。我们已经研究了MiR21，这是其中一种microRNA，发现它在大鼠肾上腺的Zona肾小球中最高表达，并与血管紧张素II孵育，并在上调。 H295R细胞中MIR21的过表达增强了对血管紧张素II的醛固酮合成，这表明MIR21在醛固酮生物合成的调节中起作用。我们最近发现了一种新的miRNA，该miRNA通过我们克隆的非编码RNA在大鼠zona glomerulosa中表达，该miRNA由血管紧张素II高度调节。我们的假设是：“调节编码醛固酮合酶的CYP11B2基因的转录和翻译的基因，并直接或直接或间接调节醛固酮生物合成。此外，“ MicroRNA调节肾上腺Zona glomerulosa细胞增殖和分化，导致Zona glomerulosa重塑，以应对生理需求，例如钠剥夺。提出了以下具体目的来检验这些假设：1。研究在大鼠zona glomerulosa功能性微阵列筛查中鉴定出的miRNA的表达，并研究在肾上腺衰减，血管紧张素II，Acth Infusion和Acth inscommenal and Adsistimal和Actorment and Acmisting和Actormenal and Acmisment and and Commisting ty诱导的肾上腺重塑期间最有前途的候选miRNA的调节。 2。表征参与H295R肾上腺皮质癌细胞系中醛固酮合酶和/或醛固酮生物合成的调节的miRNA。公共卫生相关性：醛固酮主义是次要高血压的最常见形式，占全世界未选择的患有高血压患者的7-10％。除了升高血压外，即使相对温和的醛固酮水平超出了生理需求的水平，也与与没有过多醛固酮过多的血压升高相关的心血管，肾脏和脑血管病理学更大。治疗仍然限于矿物皮质激素受体拮抗剂。识别肾上腺重塑和醛固酮产生的基因将使我们能够直接解决特发性催眠核酸的发病机理。像许多内分泌和内分泌激素驱动的器官一样，肾上腺皮质的细胞必须增殖，调节激素合成并响应不断变化的生理环境和需求，并经历凋亡。 miRNA的科学还很年轻。这种类型的翻译调节剂在其他自然会经历细胞数，大小和代谢活性的循环变化的系统中很重要，因此，这些疾病的病因，尤其是癌症，对医疗保健非常重要，并且对医疗保健至关重要。 该提案的固有优势在于调查人员团队的广泛经验。提出的实验通过初步数据进一步加强，其中包括最近的内分泌学上出版物，该数据为醛固酮分泌的miRNA依赖性调节提供了令人信服的证据。然而，对研究计划的一些担忧，包括建议进行调查的miRNA数量，再加上缺乏努力如何集中的详细策略，缺乏关键试剂（评估醛固酮合酶和11B-羟基羟基蛋白表达的抗体），以及缺乏对许多人的限制进行限制，以实验的限制。