Race and control of tissue renin angiotensin systems

描述：(根据申请者的摘要改编)高血压在黑人中比在高加索人中更普遍，并且不成比例地严重，导致更高的临床并发症发生率。总体假设是，黑人体内组织血管活性增加，通常归因于“种族”本身，实际上是由可识别的遗传因素决定的。RAAS中的候选基因包括血管紧张素原、AT1受体、醛固酮合成、11-羟基类固醇脱氢酶和血管紧张素转换酶。血管紧张素Ⅱ活性增加的表型可能与血管扩张途径活性降低(初步数据突出了激肽释放酶系统中的种族差异)、将激肽释放酶和内皮一氧化氮合酶(ENOS)添加到候选基因列表中有关。他们计划使用生理学和药理学工具来支持这一假设，专门采用特殊的招募方法来招募大量的黑人受试者。特别是在黑人中，环境因素对高血压的发展和维持的交互作用不容忽视。我们计划探索可能与高血压遗传易感性相互作用的三个因素。第一个是肥胖，已经被证明可以预测对血管紧张素原的异常肾脏反应，其影响取决于血管紧张素原基因。最有可能与基因相互作用的元素是饮食中的钾；在黑人中，尿钾通常较低，钾同样密切参与组织激肽释放酶-激动素系统的控制。最后，我们的初步证据表明，在高加索人中，描述Angii肾上腺反应迟钝的一个显著特征--性二型性--在黑人中缺失。年轻的黑人女性尤其缺乏年轻白人女性的保护，这可能是黑人女性心血管疾病死亡率较高的原因。他们假设，黑人的遗传差异调节了雌激素对RAAS的影响，可能是通过干扰其与雌激素反应元件的结合，从而影响基因转录。

DESCRIPTION: (Adapted from the applicant's abstract) Hypertension is more prevalent in blacks than in Caucasians and is disproportionately severe, leading to a higher rate of clinical complications. The overall hypothesis is that the increased tissue AngII activity in blacks, usually attributed to "race" itself, is actually determined by identifiable genetic factors. Candidate genes within the RAAS include angiotensinogen, the AT1 receptor, aldosterone syntheses, 11-OH-steroid dehyodrogenase and angiotensin-converting enzyme. The phenotypes of increased AngII activity may be compounded by decreased activity of vasodilator pathways (preliminary data highlight racial differences in the kallikreinkinin system), adding kallilrein and endothelial nitric oxide syntheses (eNOS) to the list of candidate genes. They plan to use physiologic and pharmacologic tools to support this hypothesis, devoting special recruitment methods to enroll large numbers of black subjects. Especially among blacks, the interacting contribution of environmental factors to the development and maintenance of hypertension cannot be ignored. We plan to explore three factors that may interact with genetic predisposition to hypertension. The first is obesity, already shown to predict abnormal renal responses to AngII, with its effect dependent upon angiotensinogen genotype. The most likely elemental candidate interacting with genotype is dietary potassium; urinary potassium has often measured lower among blacks, and potassium is likewise intimately involved in control of the tissue kallikrein-kinin system. Finally, our preliminary evidence suggests that a salient feature describing blunted AngII adrenal responsiveness among Caucasians - a sexual dimorphism - is absent among blacks. Young black women in particular lack the protection seen in young white women, which may underlie the higher cardiovascular morality rates seen in black women. They hypothesize that genetic differences in blacks modulate estrogen's effect on the RAAS, perhaps by interfering with its binding to estrogen response elements and therefore gene transcription.