高尿酸血症通过调控肾上皮钠通道(ENaC)介导盐敏感性高血压的机制研究

大量的临床证据表明，高尿酸血症与高血压，尤其是盐敏感性高血压的发生发展密切相关；但是二者之间内在的联系至今尚未阐明。肾脏上皮细胞钠离子通道(Epithelial Na+ channel,ENaC)的过度激活(gain-of-function)是多种类型高血压发病的重要因素之一。本课题的前期结果提示，高尿酸血症诱发大鼠高血压；明显的增加肾组织ENaC的表达；肾脏集合管上皮细胞ENaC的表达也对尿酸刺激呈浓度依赖性的上调；此外尿酸可诱发ENaC调控复合体 (ERC) 中SGK1和GILZ1的激活；抑制ERK和p38的磷酸化。这些结果均提示尿酸诱发高血压可能的机制是尿酸参与调控ENaC的表达和功能。本课题将利用在体实验和体外实验两个模型，动态观察高尿酸血症大鼠与盐敏感性高血压发生发展的内在联系；也深入探讨尿酸调控ENaC的表达及其可能的分子机制，为今后有效防治高尿酸血症及其并发症奠定理论基础。

It is evident that hyperuricemia is closely associate with high prevalence of hypertension. Approximately 50% of hypertensive individals are salt-sensitive hypertension. The interaction of hyperuricemia with salt-sensitive hypertension is still unclear. The kidney has a central role in the regulation of blood pressure, in large part through its role in the regulated resorbstion of filtered Na+. The epithelial Na+ channel (ENaC) is a key Na+ transporter in this segment of the nephron. Our preliminary data has shown the mice and rat with hyperuricemia demonstrate a significant high blood pressure and obviously incresed ENaC expression. The results from in vitro study have shown that uric acid elicited significant, dose-dependent increases in the expression of ENaC, SGK1 as well as GILZ1 which is central player of ENaC regulatory complex (ERC). Those findings implicated that hyperuricemia is key factor on hypertension, and its regulation of ENaC is potential mechanism pathway which Uric acid contributes to high blood pressure with. In the future work of this project, we will further explore the potential mechanism of high uric acid on hypertension, especailly salt-sensitive hypertension. The studies (in vivo) will be performed to examine whether hyperuricemia plays a important role in salt-sensitive hypertension using rat model. We will test other three specific aims in mouse cortical collecting duct (mCCD) cells (in vitro): (1) to define the role of uric acid in ENaC expression and function; (2) to examine whether uric acid has effect on ENaC regulatory complex (ERC); and (3) to evaluate the interactions among ERC components with uric acid stimulation in mCCDs. Successful completion of this proposal will advance our understanding of molecular mechanism of uric acid on ENaC regulation and provide a roadmap for identifying novel potential therapeutic targets to hyperuricemia and salt-sensitive hypertension.