Mcoln3在盐敏感高血压肾脏钠代谢紊乱中的作用及调控机制研究

Renal dysfunctional metabolism of sodium play a key role in formation of salt sensitivity. The renal different genes of Dahl salt sensitive rat were screened using Genechip method in our previous study.Herein, we hypothesized that Mcoln3 may be the trigger point of renal dysfunctional metabolism of sodium in salt sensitive subjects for the first time, to our knowledge.Firstly, using the animal models of Dahl salt sensitive rat and varitint-waddler mice, we explore the effect of Mcoln3 in salt induced elevation of blood pressure and the assosication between Mcoln3 and RAAS system or SGK1-ENaC pathway through drug intervention.Then, the relationships would be confirmed by RNA interference in cell level. At last, the interaction between common variation in Mcoln3 and blood pressure responses to dietary sodium interventions would be conducted , based on the collected specimen in our previous study.We believe that this work would been of great significance to uncover the etiology of salt sensitive hypertension as well as to seek another drug targets for treatment of essential hypertension.

肾脏钠代谢障碍是盐敏感性高血压形成的重要环节。本课项目在我们前期采用基因芯片筛选首次发现高盐负荷可导致Dahl盐敏感大鼠肾脏Mcoln3表达异常增高的基础上，提出"Mcoln3异常是盐敏感者肾脏钠代谢相关基因表达紊乱的重要环节"的假设，首先在动物水平上对Dahl盐敏感大鼠和varitint-waddler小鼠进行药物干预，研究肾脏Mcoln3表达对血压的影响，以及RAAS系统、SGK1-ENaC通路相关基因表达与Mcoln3的关系；进一步在细胞水平上采用RNAi方法验证Mcoln3与RAAS系统、SGK1-ENaC通路间的调节关系；最后依托我们既往收集的盐敏感队列资料和DNA样本，采用Taqman MGB探针技术结合遗传学方法探索Mcoln3基因多态性与人群个体血压对盐干预不同反应性间的关系。本研究对进一步揭示盐敏感性高血压的分子遗传学机制，寻找新的高血压药物靶点具有重要意义。

肾脏钠代谢障碍是盐敏感性高血压形成的重要环节。本课项目提出“Mcoln3异常是盐敏感者肾脏钠代谢相关基因表达紊乱的重要环节”的假设，首先在动物水平上对Dahl盐敏感大鼠进行钠钾饮食干预及药物干预，研究高盐后Dahl盐敏感大鼠Mcoln3表达明显增高，给予Gadolinium抑制Mcoln3后，血压下降，同时SGK1-ENaC的mRNA及蛋白表达水平也明显下调，以及RAAS系统无明显变化，提示Mcoln3可能主要通过调节肾脏SGK1-ENaC通路发挥调节血压作用；进一步在细胞水平上采用RNAi方法抑制Mcoln3后发现Mcoln3位于SGK1 ENaC通路上游，可通过SGK1 ENaC通路调节肾脏钠钾代谢；最后依托我们既往收集的盐敏感队列资料和DNA样本，采用Taqman MGB探针技术结合遗传学方法发现Mcoln3、SGK1及WNK1基因多态性与人群个体血压对盐干预不同反应性间存在关联。本研究对进一步揭示盐敏感性高血压的分子遗传学机制，寻找新的高血压药物靶点具有重要意义。