Renalase调控高盐诱导Necroptosis抑制盐敏感靶器官损伤作用及机制研究

High-salt intake is significantly associated with hypertension, and it also can cause target organ damage independent of blood pressure elevation. Necroptosis is a newly found type of programmed cell death that is regulated by several specific genes. Renalase that is secreted by the kidneys is reported to inhibit cell necrosis and protects target organs from injury. Through Dahl salt-sensitive rats and an interventional study, we found that high salt could induce necroptosis in HK-2 cells, and thus caused cell necrosis, which could be reversed by recombinant Renalase protein. Herein, we put forward the hypothesis “Renalase protected high-salt induced injury by inhibiting necroptosis in salt-sensitive subjects”. Firstly, using the animal models of Dahl salt-sensitive rats, knockout mice, we investigate the role of necroptosis in target organ injury in salt-sensitive rats. Additionally, we further explore the regulatory effects of Renalase on necroptosis and its possible molecular mechanisms. Finally, the relationship between polymorphisms of necroptosis related genes and blood pressure responses to dietary sodium 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.

高盐摄入与高血压关系密切，还可独立于血压对靶器官造成损伤。最新研究发现，Necroptosis是一种通过特定基因调控新的细胞程序性死亡模式；肾脏分泌的Renalase能够抑制细胞坏死、保护靶器官损伤。本项目在我们研究发现高盐诱导HK-2细胞Necroptosis发生，导致细胞坏死；而Renalase可以逆转上述改变的基础上，提出“Renalase通过调控Necroptosis抑制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Necroptosis在盐敏感靶器官损伤中的作用；进一步探究Renalase对Necroptosis发生的调控作用及其可能的分子机制；最后依托我们收集的盐敏感队列DNA样本，探索Necroptosis相关基因多态性与血压对盐干预反应性的关系。本研究对揭示盐敏感靶器官损伤的分子机制，寻找新的高血压药物靶点具有重要意义。

高盐摄入是原发性高血压的重要危险因素，且可独立于血压造成机体靶器官损害，发病机制至今尚未完全明确。Necroptotsis是一种可被调控的新型细胞坏死及凋亡方式，已被证实在多种疾病的发病及进展中发挥作用。然而高盐摄入与Necroptotsis之间的关联目前尚未见报道。本课题组在既往盐敏感性靶器官损伤发病机制的基础上，提出“Renalase调控高盐诱导Necroptosis抑制盐敏感靶器官损伤”的假设。首先，对RNLS-/-基因敲除小鼠及C57BL/6小鼠进行饮食干预，发现高盐可诱导心、肾靶器官损害，组织中Necroptotsis标志物RIP1、RIP3、MLKL蛋白及炎症因子IL-6、TNF-α等表达显著升高，同步补充肾胺酶后，靶器官损害得到改善，组织中坏死标志物及炎症因子水平也明显降低。其次，以HK-2细胞及H92c细胞为研究对象，发现肾胺酶可以凭借剂量依赖的方式显著降低Necroptotsis标志物的表达。此外，在动物和细胞水平上发现肾胺酶还可以通过调控Akt信号通路抑制炎症反应和氧化应激发挥对高盐诱导的盐敏感肾脏损伤的保护作用。再者，通过综合生物信息分析以及对人群进行慢性盐负荷饮食干预，识别血压盐敏感性的潜在生物标志物。最后，基于既往建立的“汉中青少年高血压队列”，评估BMI/BP的演变轨迹、长期变异性或累积负荷对成人亚临床靶器官损害的影响。本研究旨在探讨在高盐介导下盐敏感性靶器官损伤的发生机制以及肾胺酶对靶器官的保护作用，为今后盐敏感性靶器官损伤的治疗提供理论依据及潜在干预靶点。