"盐记忆"效应在盐敏感性高血压形成及靶器官损伤中的作用及机制研究

High-salt diet causes high blood pressure and target organ damage. On the basis of our previous study of pathogenesis of salt-sensitive hypertension, we hypothesized that in salt-sensitive subbjects, short-term high salt loading induced "salt memory", increasing oxidative stress, inflammation levels and RAAS system in local tissues, which eventually lead to sustained elevation of blood pressure and target organ damage. Firstly, to investigate whether "salt memory" existed, and the mechanism of target organ damage by oxidative stress, inflammation and RAAS system, salt-sensitive rats were fed with short-term high-salt diet and then converted to a normal diet intervention. We further use different concentrations of high-salt medium alternately at the cellular level to explore the effects of "salt memory" on intracellular oxidative stress, inflammation and RAAS system. At last, we also would recuit the subjects of "the salt sensitive cohort", and maintained the dietary intervention, which would confirm the important role of "salt memory" in the development of salt-sensitive hypertension and target organ damage. We believe that this work would been of great significance to uncover the effect of the "salt memory" in the development of salt-sensitive hypertension and the target organ damage as well as to provide the potential theoretical basis and therapeutic targets for salt-sensitive hypertension in the future.

高盐摄入是原发性高血压重要的危险因素，并导致靶器官损伤。本研究在我们既往盐敏感高血压发病机制研究的基础上，提出“盐敏感者短期高盐负荷诱导机体产生“盐记忆”，增加局部组织的氧化应激、炎症水平及RAAS活性，最终导致血压的持续升高和靶器官损伤”的假设，首先对盐敏感大鼠模型进行短时高盐后转为正常饮食干预，研究“盐记忆”的血压效应，并观察其通过氧化应激、炎症反应、RAAS激活造成靶器官损伤的机制；进一步在细胞水平上采用不同盐浓度交替干预，探讨“盐记忆”对细胞内氧化应激、炎症状态及RAAS的影响；最后在既往建立的盐敏感人群队列中进行饮食干预，进一步验证“盐记忆”在盐敏感性高血压及靶器官损伤形成中的关键地位。本研究旨在探究“盐记忆”效应在盐敏感性高血压形成及靶器官损伤中的作用，为今后盐敏感高血压的治疗提供潜在的理论基础和干预靶点。

高盐摄入是原发性高血压的重要危险因素，驱动高血压的发生发展并导致靶器官损伤。然而短期高盐摄入是否与盐敏感者远期的血压持续升高及靶器官损伤有关，目前尚未见报道。本课题在既往盐敏感高血压发病机制研究的基础上，提出“盐敏感者短期高盐负荷诱导机体产生“盐记忆”，增加局部组织的氧化应激、炎症水平及RAAS活性，最终导致血压的持续升高和靶器官损伤”的假设。首先以Dahl盐敏感性大鼠和SS-13BN大鼠为模型，结果发现在盐敏感性高血压中存在“盐记忆”效应，且氧化应激在“盐记忆”所致盐敏感内皮功能损伤中发挥重要作用；其次，通过动物实验和细胞研究发现ERRα、Mcoln3参与高盐介导盐敏感高血压的形成，同时ERRα-ENaC表达异常、Mcoln3/SGK1/ENaC通路可能是盐介导血压升高的重要机制；再者，通过对人群进行慢性盐负荷和补钾饮食干预，识别盐敏感性相关生物标志物；最后，基于人群队列的纵向随访数据，识别生命早期BP/BMI的演变轨迹，发现上述轨迹与远期血压变化或成年阶段肾脏早期损伤存在关联。以上结果进一步阐明了盐敏感性高血压的发生机制，并为原发性高血压的人群防治提供了理论基础和新策略。