Role of Dopamine D2 Receptor in Renal Inflammation and Injury

描述（由申请人提供）：慢性肾脏疾病的患病率在全球范围内急剧上升，影响美国13.1%的人口。高血压是肾损害的主要原因之一。低度炎症与心血管疾病有关，特别是与高血压有关。炎症和氧化应激是肾脏疾病发生和进展的主要介质。越来越多的证据表明，遗传因素有助于与高血压相关的肾脏疾病的易感性，并且已经表明，高血压可能仅在遗传易感个体中引起进行性肾脏疾病。慢性肾脏疾病的遗传易感性是多基因的，但到目前为止，只有少数基因已被证明是贡献。该项目将测试多巴胺D2受体调节肾脏炎症反应以及D2受体功能受损导致肾脏炎症和终末器官损伤的整体新假设。D2受体基因的多态性通常在人类中观察到，其中一些与血压升高甚至高血压有关。D2受体的几种多态性导致受体的表达/功能降低。如果我们的假设被证明是正确的，那么携带这些多态性的个体在受到诸如血压升高之类的损害时可能更容易受到肾损伤。这些结果对于设计创新的基因检测和治疗方法至关重要。 公共卫生相关性：遗传因素导致原发性高血压相关肾脏疾病的易感性。炎症在肾损伤的发展中至关重要。该项目将测试多巴胺D2受体功能受损导致肾脏炎症和终末器官损伤的整体新假设。D2受体的几种多态性导致受体表达降低或受体亲和力降低。如果我们的假设被证明是正确的，那么携带这些多态性的个体可能更容易受到肾损伤。

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. PUBLIC HEALTH RELEVANCE: Genetic factors contribute to the susceptibility to renal disease associated with essential hypertension. Inflammation is crucial in the development of renal injury. This project will test the overall novel hypothesis that impaired function of the dopamine D2 receptor results in renal inflammation and end-organ damage. Several polymorphisms of the D2 receptor result in decreased expression of the receptor or decreased receptor affinity. If our hypothesis proves to be correct, then individuals carrying these polymorphisms could be more vulnerable to renal injury.