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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：最近的肥胖症流行，影响全世界的女性更多，是高血压的主要危险因素，是年轻成年女性高血压患病率增加三倍的原因。尽管研究了数十年的研究机制调节性血压，但数以百万计的妇女的高血压治疗不足，这主要是由于缺乏对机制调节性血压的性别特异性的了解。在该提案的初步研究中，我们进行了重大观察，这些观察给这个问题带来了重大启示。首先是肥胖引起的女性的高血压与男性的进展不同，涉及血浆醛固酮的瘦素介导的增加。醛固酮的封锁不成比例地降低了肥胖雌性小鼠与雄性的血压。第二个观察结果是对醛固酮分泌的新部位和调节剂的潜在鉴定。人，啮齿动物和细胞证据表明，瘦素可以直接控制肾上腺和脂肪组织中的醛固酮分泌。最后的观察结果是，雌激素的存在可能在女性中诱发的醛固酮分泌。实际上，用卵巢切除术清除雌激素可以废除瘦素和醛固酮之间的相关性。在当前的提案中，我们将以三个目标严格测试这些概念。第一个目的将结合肥胖的病理生理模型与新型瘦素受体拮抗剂的使用，以识别肥胖雌性小鼠血压的机制。第二个目标将就业药理和细胞方法来确定雌激素在瘦素介导的醛固酮分泌中的作用。第三个目的将在体内假设这些概念，以测试雌激素去除是否消除了肥胖雌性小鼠血压的机制的醛固酮依赖性。这些研究一起将提供有关应对血压的机制的性别特异性的新信息，并可能确定一种新的信号通路，导致醛固酮的合成。这些目标的成功完成可能会确定妇女与肥胖相关的高血压的新治疗策略，并提供基于性别的治疗肥胖诱导高血压的治疗策略所需的原则证明。