尿液中血管紧张素原等生物标志物与血压盐敏感性及高血压发病的关系

Hypertension is the leading risk for cardiovascular disease. Salt-sensitivity of blood pressure (BP) is associated with increased risk of hypertension and cardiovascular disease mortality, but the underlying mechanism of salt-sensitivity is not fully understood. As the largest family based dietary feeding-study related to salt-sensitivity of BP, the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study was conducted to test the BP responses to the dietary interventions which included a 7-day low-sodium feeding (51.3 mmol per day), a 7-day high-sodium feeding (307.8 mmol per day), and a 7-day high-sodium plus potassium supplementation (60 mmol per day). Prospective follow up study of incident hypertension and replication study in an independent population were conducted in subsequent years. Based on our previous study with high quality data, blood and urine samples, the proposed study is to investigate the association between urinary excretions of novel biomarkers with salt- and potassium-sensitivity of BP, as well as prospective association with incident hypertension. To achieve this goal, we will determine urinary angiotensinogen, kallikrein, dopamine, and norepinephrine through ELISA and RIA methods and analyze the association of urinary excretion of biomarkers at baseline with BP responses to dietary sodium and potassium interventions among a total of 2604 participants. We will also analyze the prospective relationship between urinary excretion of biomarkers at baseline and risk of hypertension using GenSalt follow-up data. In summary, the proposed study will be the first large investigation to examine the association between multiple urinary biomarkers and risk of BP salt- and potassium-sensitivity and incident hypertension. The findings from this study may provide novel insights into the underlying biologic mechanisms of salt-sensitivity and potassium-sensitivity of BP. Our findings may also help to identify novel biomarkers for the prediction of hypertension risk.

高血压是最重要的心血管疾病危险因素，血压盐敏感性可显著增加高血压发病风险和心血管疾病死亡率，但其病理生理机制仍不明确。本课题组前期开展的全球规模最大的血压盐敏感性膳食干预试验GenSalt 研究，评价不同膳食干预（低盐、高盐、高盐补钾）对2604 例研究对象血压的影响，并开展了高血压发病前瞻性随访和独立人群重复验证研究，收集了高质量的数据和血液、尿液样本。本课题旨在探索尿液中新型生物标志物与血压盐敏感性、钾敏感性及高血压发病之间的关系。为此，我们将采用ELISA 法和RIA 法测定研究对象尿液中的血管紧张素原、激肽释放酶、多巴胺、去甲肾上腺素含量，分析其与血压盐敏感性和钾敏感性的关系；利用前瞻性随访结果分析其与高血压发病的关系。本研究是首次在一般人群中探索尿液中多种生物标志物与血压盐敏感性、钾敏感性的关系，将为阐明血压调节的生物机制提供新视角，为临床高血压发病风险的早期预警提供新证据。

肾素-血管紧张素系统（RAS）的激活在高血压的发生中起重要作用。尿液中血管紧张素原（UAGT）水平是一项评价肾内RAS系统活性的可靠指标。本项目探讨了UAGT等是否可以作为预测血压盐敏感性和钾敏感性的潜在生物标志物，及其在高血压发生中的作用及可能遗传机制。.项目基于GenSalt膳食干预研究，收集基线、低盐、高盐、高盐补钾干预阶段末的尿标本。所有研究对象随访约7.2年，观测高血压及心血管病发病情况。利用酶联免疫试剂盒测定24小时UAGT等指标。分析发现UAGT和尿血管紧张素原/肌酐比（UAGT/Cr）在低盐和高盐补钾阶段显著降低，在高盐阶段显著增加。基线阶段UAGT和UAGT/Cr比值与基线和每次干预结束时的血压水平显著正相关。UAGT/Cr比值每升高一个标准差，高盐阶段末收缩压升高5.0mmHg，从低盐到高盐阶段收缩压变化差值增加1.6mmHg。UAGT和UAGT/Cr比值与盐敏感性的相关性相似。UAGT升高与血压钠敏感性有关，RAS系统活性增强可能在盐敏感性高血压的发生中起重要作用。.项目分析了RAS系统中10个基因与血压变化及高血压发病的关系，结果显示盐皮质激素受体编码基因NR3C2的变异位点与收缩压的长期变化显著相关。NR3C2基因编码的盐皮质激素受体是醛固酮在体内发挥其主要作用的受体。因此RAS系统NR3C2基因可能在我国人群高血压的发生发展中起重要作用。.另外研究还发现限盐和补钾干预能显著降低中心动脉压及中心增强指数，可能对代谢危险因素聚集的患者更有效。G蛋白介导的钾离子内流通道（GIRK）编码基因KCNJ6、环鸟苷酸依赖的蛋白激酶1（PRKG1）和烟酰胺腺嘌呤二核苷磷酸（NADPH）氧化酶相关基因RAC1基因变异与血压盐敏感性相关，NADPH氧化酶相关基因NCF2基因变异与血压的长期变化有关，提示这些基因可能在高血压的发生中起重要作用。.本研究从检测尿液中生物标志物的视角，为临床识别盐敏感性高血压个体提供简便有效的检测办法，为高血压高危人群采用饮食干预及降压治疗、以及高血压的发病预测提供依据，也有助于阐明血压盐敏感性和钾敏感性的病理生理机制。