Ferroptosis介导盐敏感靶器官损害及Renalase的保护机制研究

高盐摄入导致高血压，还可独立于血压造成靶器官损伤。新近研究发现，Ferroptosis是一种铁依赖的新型程序性死亡；肾脏分泌的Renalase具有抑制组织细胞损伤、保护靶器官作用。本项目在我们研究发现高盐能够激活Nrf2/HO-1/GPX4通路，促进Ferroptosis发生，而Renalase可以逆转上述改变的基础上，提出“Renalase通过抑制Ferroptosis保护高盐诱导盐敏感靶器官损伤”的假设。首先拟采用Dahl盐敏感大鼠、基因敲除小鼠，在动物水平研究Ferroptosis在盐敏感靶器官损伤中的作用；进一步探究Renalase对Ferroptosis发生的调控作用及其可能分子机制。最后依托我们建立的盐敏感队列，探索Ferroptosis相关基因多态性与个体盐敏感性、人群远期靶器官损伤的关系。本研究对揭示盐敏感高血压靶器官损伤的分子机制，寻找新的干预靶点具有重要意义。

High salt intake not only leads to hypertension, but also causes target organ damage (TOD) independently of blood pressure elevation. Recent studies show that Ferroptosis is a new type of iron-dependent programmed death; Renalase secreted by the kidney can inhibit tissue damage and protect target organ damage. Through our preliminary experiments, we found that high salt can activate the Nrf2 / HO-1 / GPX4 pathway and promote the Ferroptosis, while Renalase can reverse these changes. Herein, we put forward the hypothesis “Renalase improved TOD by inhibiting high-salt-induced Ferroptosis in salt-sensitive subjects”. Firstly, using the animal models of Dahl salt-sensitive rats, knockout mice, we investigate the role of Ferroptosis in TOD in salt-sensitive rats. Additionally, we further explore the regulatory effects of Renalase on Ferroptosis and its underlying molecular mechanism. Finally, the relationship of polymorphisms of Ferroptosis related genes with blood pressure responses to dietary sodium and long-term TOD were assessed based on the DNA samples of the salt-sensitive cohort in the previous study. We believe that this work would be of great significance to uncover the molecular mechanism of target organ damage in salt-sensitive subjects as well as to provide the potential therapeutic targets for hypertension in the future.