Role of Dopamine D2 Receptor in Renal Inflammation and Injury

描述(申请人提供)：慢性肾脏疾病的患病率在全球范围内急剧上升，影响到美国13.1%的人口。高血压是肾脏损伤的主要原因之一。低度炎症与心血管疾病有关，尤其与高血压有关。炎症和氧化应激是肾脏疾病发生和发展的主要介质。越来越多的证据表明，遗传因素与高血压相关的肾脏疾病的易感性有关，而且已有证据表明，高血压可能只在遗传易感个体中导致进行性肾脏疾病。慢性肾脏疾病的遗传易感性是多基因的，但到目前为止，只有几个基因被证明是有贡献的。这个项目将测试整个新的假设，即多巴胺D2受体调节肾脏的炎症反应，以及D2受体的功能受损导致肾脏炎症和终末器官损伤。D2受体基因的多态性在人类中很常见，其中一些与高血压甚至高血压有关。D2受体的几个多态导致该受体的表达/功能降低。如果我们的假设被证明是正确的，那么携带这些基因多态性的人在受到诸如高血压等侮辱的挑战时可能更容易受到肾脏损伤的影响。这些结果可能对设计创新的基因测试分析和治疗方法至关重要。

DESCRIPTION (provided by applicant): The prevalence of chronic kidney disease is rising sharply worldwide and affects 13.1% of the population in the USA. Hypertension is one of the major causes of renal injury. Low-grade inflammation is associated with cardiovascular disease and specifically with hypertension. Inflammation and oxidative stress are major mediators in the development and progression of renal disease. There is increasing evidence that genetic factors contribute to the susceptibility to renal disease associated with hypertension and it has been suggested that hypertension may cause progressive kidney disease only in genetically susceptible individuals. The genetic predisposition to chronic kidney disease is polygenic but so far only a few genes have been shown to be contributory. This project will test the overall novel hypothesis that the dopamine D2 receptor regulates the inflammatory reaction in the kidney and that impaired function of the D2 receptor results in renal inflammation and end-organ damage. Polymorphisms of the D2 receptor gene are commonly observed in humans and some of them have been associated with elevated blood pressure and even hypertension. Several polymorphisms of the D2 receptor result in decreased expression/function of the receptor. If our hypothesis proves to be correct, then individuals carrying these polymorphisms could be more vulnerable to renal injury when challenged with an insult such as elevated blood pressure. These results could then be critical for designing innovative genetic testing assays and therapeutics.