Aldosterone Contribution to Leptin-mediated Hypertension in Obese Females

醛固酮对肥胖女性瘦素介导的高血压的影响

• 批准号: 9199106
• 负责人: Eric J Belin de Chantemele
• 金额: $ 38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199106
• 关键词: Adipocytes; Adipose tissue; Adrenal Glands; Affect; Aldosterone; Blood Pressure; CYP11B2 gene; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cells; Clinical Data; Clinical Research; Data; Dependence; Epidemic; Estrogen Replacement Therapy; Estrogens; Excision; Female; Genetic Engineering; Genetic Models; Health; Hormones; Human; Hypertension; In Vitro; Knowledge; Leptin; Light; Link; Mediating; Mineralocorticoids; Modeling; Mus; Obesity; Obesity Related Hypertension; Outcome; Ovariectomy; Pharmacology; Phenotype; Plasma; Premenopause; Prevalence; Production; Radio; Research; Risk Factors; Rodent; Role; Signal Pathway; Signal Transduction; Site; Specificity; Telemetry; Testing; Therapeutic Clinical Trial; Thinness; Time; Western World; Withdrawal; Woman; base; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; eplerenone; experimental study; in vivo; instrument; leptin receptor; male; men; novel; novel therapeutic intervention; pressure; public health relevance; sex; young adult

 DESCRIPTION (provided by applicant): The recent obesity epidemic, which affects more women than men worldwide, is a major risk factor for hypertension and the cause of a three-fold increase in the prevalence of hypertension in young adult women. Despite decade of research investigating the mechanisms regulating blood pressure, millions of women remain inadequately treated for hypertension largely due to a lack of understanding of the sex-specificity of the mechanisms regulating blood pressure. In preliminary studies for this proposal, we have made major observations that shed significant new light on this issue. The first is that obesity-induced hypertension in females progresses differently from males and involves leptin-mediated increases in plasma aldosterone. Blockade of aldosterone disproportionately lowers blood pressure in obese female mice versus males. The second observation is the potential identification of novel site and regulator of aldosterone secretion. Human, rodent, and cell evidence indicate that leptin exerts a direct control of aldosterone secretion in adrenal glands and adipose tissue. The last observation is that leptin-induced aldosterone secretion is potentiated in females, by the presence of estrogen. Indeed, estrogen removal with ovariectomy abolishes the correlation between leptin and aldosterone. In the current proposal, we will rigorously test these concepts in three aims. The first aim will combine the use of pathophysiological models of obesity with a novel leptin receptor antagonist to identify the mechanisms regulating blood pressure in obese female mice. The second aim will employ pharmacological and cellular approach to determine the role of estrogen in leptin-mediated aldosterone secretion. The third aim will purse these concepts, in vivo, testing whether estrogen removal abolishes the aldosterone dependence of the mechanisms regulating blood pressure in obese female mice. Taken together these studies will provide new information on the sex-specificity of the mechanisms regulating blood pressure and will likely identify a new signaling pathway leading to the synthesis of aldosterone. Successful completion of these aims may identify new therapeutic strategies for obesity-related hypertension in women and provide the proof of principle required for sex-based clinical trials of therapeutic strategies to treat obesit-induced hypertension.

 描述（由申请方提供）：最近的肥胖流行病，在全球范围内影响女性多于男性，是高血压的主要风险因素，也是年轻成年女性高血压患病率增加三倍的原因。尽管对调节血压的机制进行了数十年的研究，但数百万妇女仍然没有得到充分的高血压治疗，这主要是由于缺乏对调节血压机制的性别特异性的了解。在对这一建议的初步研究中，我们提出了一些重要的意见，为这一问题提供了重要的新线索。首先是肥胖引起的 女性高血压的进展与男性不同，并且涉及瘦素介导的血浆醛固酮增加。阻断醛固酮不成比例地降低肥胖雌性小鼠的血压。第二个观察是潜在的新网站和醛固酮分泌调节剂的鉴定。人类、啮齿动物和细胞证据表明，瘦素直接控制肾上腺和脂肪组织中的醛固酮分泌。最后一个观察结果是，瘦素诱导的醛固酮分泌在女性中由于雌激素的存在而增强。事实上，卵巢切除术去除雌激素消除了瘦素和醛固酮之间的相关性。在当前的提案中，我们将在三个目标中严格测试这些概念。第一个目标将联合收割机结合使用肥胖症的病理生理学模型与一种新的瘦素受体拮抗剂，以确定调节肥胖雌性小鼠血压的机制。第二个目标将采用药理学和细胞的方法来确定雌激素在瘦素介导的醛固酮分泌中的作用。第三个目标将在体内研究这些概念，测试雌激素去除是否消除了肥胖雌性小鼠血压调节机制的醛固酮依赖性。总之，这些研究将提供关于调节血压机制的性别特异性的新信息，并可能确定导致醛固酮合成的新信号通路。这些目标的成功完成可能会发现新的治疗策略，肥胖相关的高血压的妇女和提供的原则证明，需要基于性别的临床试验的治疗策略，以治疗肥胖引起的高血压。