Aldosterone Contribution to Leptin-mediated Hypertension in Obese Females

 描述(申请人提供)：最近的肥胖症流行，影响世界各地的女性比男性更多，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。尽管对血压调节机制进行了十年的研究，但数百万女性仍然没有得到充分的高血压治疗，这主要是因为缺乏对血压调节机制的性别特异性的了解。在对这项提议的初步研究中，我们提出了一些重要意见，为这一问题提供了重要的新线索。第一个是由肥胖引起的 女性高血压的进展与男性不同，涉及瘦素介导的血浆醛固酮升高。与雄性相比，阻断醛固酮可以不成比例地降低肥胖雌性小鼠的血压。第二个观察是对醛固酮分泌的新部位和调节因子的潜在鉴定。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，在雌激素的存在下，女性体内瘦素诱导的醛固酮分泌会增强。事实上，卵巢切除去除雌激素消除了瘦素和醛固酮之间的相关性。在目前的提案中，我们将从三个目标严格检验这些概念。第一个目标是将肥胖的病理生理学模型与一种新的瘦素受体拮抗剂相结合，以确定肥胖雌性小鼠的血压调节机制。第二个目标将使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测试雌激素去除是否消除了肥胖雌性小鼠血压调节机制对醛固酮的依赖。综上所述，这些研究将为血压调节机制的性别特异性提供新的信息，并可能确定导致醛固酮合成的新信号途径。这些目标的成功完成可能会确定女性肥胖相关高血压的新治疗策略，并为基于性别的治疗策略治疗顺式高血压的临床试验提供所需的原则证明。

 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.