嘌呤受体P2X4在盐敏感性高血压和肾损害中的作用研究

Hypertension has been identified as the leading risk factor for mortality, a new analysis shows that in 2000 more than a quarter of the world's population (a number totaling nearly one billion) was hypertensive and suggests that by 2025, that number will climb to 29%, or about 1.56 billion people worldwide, and then to estimate the global burden. Persistent hypertension is one of the risk factors for stroke, myocardial infarction, heart failure and arterial aneurysm, and is a leading cause of chronic kidney failure. The global burden of high blood pressure supports predictions of a worldwide epidemic of these diseases, and leads to shortened life expectancy. Thus, drug treatment may prove necessary in patients for hypertension. The P2X4 and P2X7 receptor is an ATP-gated cation channel, which is mainly expressed in immune cells, including macrophages and lymphocytes. Stimulation of the P2X4 receptor is proinflammatory and leads to the release of inflammatory cytokines. In an earlier study, we performed a genome-wide quantitative trait locus (QTL) analysis of rat blood pressure and identified a chromosome 12 around D12Arb6 marker, which is located near the P2X4 and P2X7 gene, as a region involved in the regulation of blood pressure. We also reported that P2X7 deficiency attenuates hypertension and renal injury in deoxycorticosterone acetate (DOCA)-salt hypertension, and P2X7 receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats. It is also known that P2X4 and P2X7 genetic variation significantly affects blood pressure in a Caucasian population. The pathophysiology of hypertension and renal diseases is well studied, but few studies have addressed the role of the P2X4 receptor in the progression of hypertension and renal diseases. Thus, the relevance of the P2X4 receptor to hypertension and renal injury remains to be elucidated. This study investigated the expression of P2X4 receptor in the kidney of Dahl salt-sensitive and Dahl salt-resistant rats,and the role of the P2X4 receptor in salt-sensitive hypertension. This study also investigated the role of the P2X4 receptor in the development of DOCA-salt hypertension and renal injury in wild-type (WT) and P2X4-deficient (P2X4 KO) mice. To our knowledge, this is the first study to try to demonstrate a positive relationship between P2X4 recptor and salt-sensitive hypertension. The P2X4 receptor may be an important novel therapeutic target in hypertension-induced renal injury, and this study contributes to a better understanding of P2X4 in the mechanism, prevention, and therapy for hypertension and renal injury.

我国北方地区的高血压患者绝大部分是盐敏感性高血压，所以开发针对治疗盐敏感性高血压的特效药是非常必要的。我们在以前的研究中，利用全基因组的数量性状位点（QTL）实验分析了盐敏感型高血压大鼠和盐抵抗型大鼠的血压，分析结果表明嘌呤受体P2X4的基因表达参与了调节血压。然而，P2X4受体是否真的对血压有影响以及通过什么调节机制来影响血压的，是否对肾脏具有保护作用，到目前为止，还不是很清楚。本项目拟观察两种盐敏感性高血压动物模型的血压和肾脏中P2X4受体的表达，以及肾脏中各种炎性细胞的表达，从免疫炎症的角度探讨P2X4受体在盐敏感性高血压和肾损害中的作用及可能的机制，为治疗盐敏感性高血压和肾损害提供新的思路，也为今后以P2X4受体为靶点设计新型药物提供理论依据。

我国北方地区的高血压患者绝大部分是盐敏感性高血压，所以开发针对治疗盐敏感性高血压的特效药是非常必要的。我们在以前的研究中，利用全基因组的数量性状位点（QTL）实验分析了盐敏感型高血压大鼠和盐抵抗型大鼠的血压，分析结果表明嘌呤受体P2X4的基因表达参与了调节血压。本项目发现P2X4受体（基因和蛋白水平）在盐敏感性高血压大鼠肾脏中具有高表达。当喂食高盐饲料后，盐敏感性高血压大鼠的血压升高到了180mmHg左右，P2X4受体基因和蛋白的表达量也随之升高。而且，本项目还发现建立盐敏感性高血压动物模型后，正常小鼠的血压由120mmHg升高至153mmHg左右，P2X4基因敲除小鼠的血压由124mmHg升高至140mmHg左右，P2X4基因敲除小鼠的血压与正常小鼠相比要低很多。在建立盐敏感性高血压模型后，与正常小鼠相比较，P2X4基因敲除小鼠的肾功能有所改善（尿中白蛋白减少和肌酐清除率增加）。在P2X4基因敲除小鼠肾脏中，肾纤维化面积减少，肾成纤维细胞的数量减少，各种炎性细胞的表达也减少。以上的实验结果说明P2X4受体与高血压的发生和发展有着密切的关系，P2X4受体基因缺失对盐敏感性高血压和肾损害有着重要的影响。本项目从免疫炎症的角度探讨P2X4受体在盐敏感性高血压和肾损害中的作用及可能的机制，为治疗盐敏感性高血压和肾损害提供新的思路，也为今后以P2X4受体为靶点设计新型药物提供理论依据。