TRP通道调控细胞离子稳态失衡致盐敏感高血压的机制及其干预

Salt-sensitive hypertension is the main characteristics of hypertension in China. Imbalance of intracellular ion homeostasis caused by high sodium intake plays important roles in the pathogenesis and target organ damage of hypertension. The intracellular ion homeostasis is also regulated by transient receptor potential (TRP) channels, which have been observed to localize in mitochondria. However, whether the TRP channels regulate blood pressure through participating in the imbalance of vascular and renal intracellular and mitochondrial ion homeostasis remains unclear. We have investigated the effect of cellular ion homeostasis on hypertension for a long time, and we originally observed that the dysfunction of TRPC3 resulted in hypertension and proved that TRPC3 is a candidate gene of salt-sensitive hypertension, which could be reduced by another TRPC member, TRPC6. We also found that activation of TRPA1 by diatary cinnamaldehyde inhibited hypertension through improving renal sodium excretion. Thus we hypothesize that high sodium diet would cause imbalance of intracellular and mitochondrial ion homeostasis through damaging TRPC3/6, thus result in the blood pressure elevation through stimulating several signaling pathways leading to vascular dysfunction. And activation of TRPA1 by diatary cinnamaldehyde might inhibit hypertension through improving renal cellular ion homeostasis. To investigate this hypothesis, TRPC3/6 and TRPA1 knockout mice will be used to clarify the mechanism of high sodium on hypertension caused by imbalance of vascular and renal cellular and mitochondrial ion homeostasis through regulating TRP channels in both animal and cell levels. This project will also provide specific methods for prevention and treatment of salt-sensitive hypertension through intervention of TRP channels.

盐敏感高血压是我国高血压的重要特征，高盐引起的细胞离子稳态失衡在高血压发生和靶器官损害中起重要作用。细胞离子稳态也受瞬时受体电位(TRP)通道调控，新近发现线粒体上存在TRP通道，但其是否参与细胞和线粒体离子稳态的调控并不清楚。本项目组长期研究细胞离子稳态在高血压中的作用，首先发现瞬时受体电位通道TRPC3功能异常导致高血压，并证实TRPC3是一个盐敏感高血压基因，而TRPC6对TRPC3存在抑制效应。膳食桂皮醛激活肾脏TRPA1则可促进盐的排泄而降低高血压。为此，我们提出假设：高盐可能损害TRPC3/TRPC6导致细胞及线粒体离子稳态失衡，并启动系列致血管重塑与功能失常的信号通路，导致盐敏感高血压，而干预TRPA1能通过促进尿钠排泄拮抗高盐的作用。我们拟采用TRPC3/6和TRPA1基因敲除小鼠,阐明高盐通过TRP通道致细胞和线粒体离子稳态失衡致盐敏感高血压的机制，并提出干预策略。

盐敏感高血压是我国重要的高血压类型，高盐引起的细胞离子稳态失衡造成了高血压发生和靶器官的损害。瞬时受体电位通道对维持细胞内离子稳态起着关键作用，然而，有哪些TRP通道参与盐敏感高血压的发生还不清楚。本项目主要的研究工作围绕TRP通道在盐敏感性高血压及其靶器官损害中的作用及分子机制展开，并探讨了干预TRP通道在防治盐敏感高血压中的作用，取得了以下两方面的学术成果：一、发现了TRP通道功能失常通过影响盐的摄入、吸收与排泄致盐敏感高血压的机制。我们发现长期高盐摄入通过下调一种苦味传感器TRPM5造成机体对盐的厌恶反应消失，引起盐摄入增加和血压增高。苦瓜素激活TRPM5可减少盐的摄入，降低血压。人群研究发现肥胖者对盐的敏感性降低与中枢特定脑区代谢活动增加有关，而辣椒素则作用于中枢降低了受试者的盐摄入量。并且，咖啡因具有减少盐敏感大鼠肠道钠吸收的作用，有助于降压。二、发现了盐通过影响血压调控器官心脏、血管与肾脏的TRP通道致离子稳态失衡引起血压增高的机制。我们首次发现TRPP3通道在心肌上表达并随着心肌肥厚过程表达增加，是抑制心肌肥厚的重要分子。高盐饮食能够增加心肌TRPC3的表达，而敲除TRPC3则抑制高盐引起的心肌肥厚。高血压患者外周血单个核细胞（PBMCs）中TRPC3表达水平的升高与盐摄入量和收缩压有关。我们还发现DPP-4抑制剂维格列汀能够促进TRPV4介导的瞬时钙摄取恢复血管内皮功能。在肾脏中，辣椒素激活TRPV1减轻肾小球足细胞线粒体功能障碍。而芹菜素激活肾脏中的TRPV4改善肾脏纤维化并降低盐敏感高血压。以上这些工作不仅发现了TRP通道在盐敏感性高血压发生中的作用，还提出了使用苦瓜素、辣椒素及代谢调控药物维格列汀能够通过激活TRP通道对抗盐敏感高血压的发生及其靶器官损害，为临床和人群盐敏感性高血压的防治提供了理论基础及简单易行的措施。