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（由申请人提供）：尽管经过了十年的研究，最近的肥胖流行病在全球范围内影响的女性多于男性，是高血压的主要危险因素，也是年轻成年女性高血压患病率增加三倍的原因。在调查血压调节机制时，数以百万计的女性仍然没有得到充分的高血压治疗，这主要是由于缺乏对血压调节机制的性别特异性的了解。关于这个问题。肥胖引起的雌性高血压的进展与雄性不同，涉及瘦素介导的血浆醛固酮增加，与雄性相比，醛固酮阻断可显着降低肥胖雌性小鼠的血压。，并且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。最后的观察结果是瘦素诱导的醛固酮。事实上，通过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。在当前的提议中，我们将在三个目标中严格测试这些概念。使用新型瘦素受体拮抗剂建立肥胖模型，以确定肥胖雌性小鼠血压的调节机制。第二个目标将采用药理学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。第三个目标是在体内研究这些概念，测试雌激素的去除是否可以消除肥胖雌性小鼠血压调节机制对醛固酮的依赖性。总而言之，这些研究将为血压调节机制的性别特异性提供新的信息。可能确定导致醛固酮合成的新信号通路，成功完成这些目标可能会确定女性肥胖相关高血压的新治疗策略，并为治疗肥胖的治疗策略的基于性别的临床试验提供原理证明。诱发高血压。