Project 1.Stress and African American Male Predisposition for Kidney and Cardiometabolic Disease

摘要 年轻的高血压非裔美国人(AA)男性患肾脏疾病的风险是任何人的10到14倍 其他高血压组。造成这种显著差异的原因仍不得而知。已知的是种族主义 极大地增加了AAS的疾病风险。我们的初步结果表明，应激激素系统 在AA男性中被激活，与感知到的种族主义有关，但在AA女性中不被激活。这些发现提高了 问：为什么再生障碍性贫血男性的种族主义经历会导致下丘脑-垂体-肾上腺激活 AXIS(HPA)系统和AA男性和女性对知觉的生物反应有何不同 种族主义(PR)？本项目拟对这些重要问题进行研究。传统的概念 种族主义和疾病框架表明，不适应的应对方法在感知压力和 对种族主义或压力的反应一般可以促进HPA系统的激活，而适应方法 可能会影响HPA的激活。因此，我们假设AA男性健康差距可能是由于使用 不适应的应对方法，导致HPA的激活，导致应激激素增加 醛固酮(Aldo)、皮质醇和交感神经输出，这两者都会促进心肾疾病。 众所周知，Aldo在肾脏疾病中升高；在AAs中升高；在以下情况下促进肾脏损伤 通过激活盐皮质激素受体(MR)导致盐敏感型高血压 炎症和纤维化的发生通过RAC-1通路信号传导。因此，奥尔多是一种应激激素。 这可能在这一脆弱群体的肾脏疾病差异中发挥了重要作用。为了检验我们的假设，我们 将招募AA男性和女性，并进行心理社会调查，以确定他们感知的种族主义 和压力水平；他们使用不适应应对(愤怒和敌意)；他们使用适应性应对(社会 支持)；以及他们的Aldo和皮质醇水平。我们将确定适应性应对是否起到缓冲作用 在适应不良时，Aldo和皮质醇水平的增加会促进Aldo和皮质醇水平的增加。 此外，我们将确定醛固酮和皮质醇水平是否与肾脏风险增加有关。 腹主动脉系统的损伤。我们还用动物模型证实了Aldo和皮质醇的增加会导致肾脏 高血压环境中的损害。这项研究的结果将第一次显示出潜在的 病理生理学(ALDO)将种族主义和肾脏疾病联系起来，因此，提供了新的见解 可能导致更精确的AA治疗高血压，这将阻止肾脏的发展 常与高血压有关的疾病。

ABSTRACT Young hypertensive African American (AA) males have a 10 to 14-fold greater risk for kidney disease than any other hypertensive group. The reason for this striking disparity remains unknown. What is known is that racism significantly contributes to disease risk in AAs. Our preliminary results suggest that the stress hormone system is activated in AA males in association with perceived racism but not in AA females. These findings raise the questions: why do AA males' experiences of racism result in activation of the hypothalamus-pituitary-adrenal axis (HPA) system and how are AA males and females different in their biological response to perceived racism (PR)? This project proposes to investigate these important questions. The conventional conceptual frame for racism and disease suggests that maladaptive coping methods in perception of stress and in response to racism or stress in general can promote the activation of the HPA system while adaptive methods may mititgate the HPA activation. Therefore, we posit that the AA male health disparity may result from use of maladaptive coping methods that leads to activation of the HPA resulting in increased stress hormones aldosterone (ALDO) and cortisol and sympathetic nerve output, both of which promote cardiorenal diseases. ALDO is known to: be elevated in kidney disease; be higher in AAs; and promote kidney injury in the setting of salt-sensitive hypertension by activating the mineralocorticoid receptor (MR) resulting in subsequent inflammation and fibrosis development through RAC 1 pathway signaling. Thus, ALDO is a stress hormone that likely plays a major role in the kidney disease disparity in this vulnerable group. To test our hypothesis we will recruit AA males and females and administer psychosocial surveys to determine their perceived racism and stress levels; their use of maladaptive coping (anger and hostility); their use of adaptive coping (social support); and their levels of ALDO and cortisol. We will determine whether adaptive coping acts to buffer the increase in ALDO and cortisol while maladaptive coping promotes the increase in ALDO and cortisol levels. Furthermore, we will determine if the ALDO and cortisol levels are associated with increased risk for kidney injury in AAs. We also use animal model to confirm that increased ALDO and cortisol can cause kidney damage in the setting of hypertension. The results from this study will be the first to show the underlying pathophysiology (ALDO) link between racism and kidney disease and, consequently, provide new insights that could lead to more precise treatment of AA for hypertension that will prevent the development of kidney disease that is often associated with hypertension.