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

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。

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.