Uric Acid in Childhood Hypertension

尿酸与儿童高血压

• 批准号: 6931909
• 负责人: DANIEL I FEIG
• 金额: $ 14.44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931909
• 关键词: adolescence (12-20); allopurinol; cardiovascular disorder chemotherapy; clinical research; disease /disorder onset; human subject; human therapy evaluation; hypertension; hyperuricemia; kidney transplantation; middle childhood (6-11); pathologic process; patient oriented research; renin angiotensin system; urate

DESCRIPTION (provided by applicant): An association between hyperuricemia and hypertension has been observed repeatedly since the 1870s. Generally the link was dismissed as having no causal role because of an assumption that the increase in serum uric acid was merely a surrogate for decreased glomerular filtration rate. Recently the association has been reevaluated because of results from several large clinical trials that implicate hyperuricemia as an independent risk factor for poor cardiovascular outcomes. Our own data demonstrates a close correlation between serum uric acid and primary hypertension in children. Furthermore, data from experiments using a model of mild hyperuricemia in rats reveal that the hyperuricemia alone is (1) sufficient to lead to hypertension and (2) exacerbates the progressive renal injury associated with either Cyclosporin A nephrotoxicity or surgical 5/6 nephrectomy. In the animal model, the mechanisms involved in these processes include uric acid mediated activation of cyclooxygenase-II, activation of the renin angiotensin system and down regulation of renal nitric oxide synthase. If these animal studies can be generalized to human populations, control of mild hyperuricemia will provide a new approach to management of hypertension as well as a novel therapeutic target for the prevention of progressive renal disease and cardiovascular morbidity. We propose to test whether the use of the xanthine oxidase inhibitor allopurinol, a uric acid lowering drug, will (1) ameliorate primary hypertension in children and (2) control hypertension in renal transplant recipients receiving cyclosporin or tacrolimus. We will further investigate the physiological mechanism by which serum uric acid levels are elevated in hypertensive children and the biochemical mechanisms by which elevated serum uric acid lead to increased blood pressure.

描述（由申请人提供）： 自1870年代以来，已经反复观察到高尿酸血症和高血压之间的关联。通常，由于假设血清尿酸的增加仅仅是肾小球滤过率降低的替代物，因此该连接被认为没有因果作用。最近，由于几项大型临床试验的结果，该关联被重新评估，这些试验暗示高尿酸血症是较差的心血管结局的独立危险因素。我们自己的数据表明，血清尿酸与儿童初次高血压之间的密切相关。此外，使用大鼠轻度高尿素模型的实验数据表明，单独的高尿酸血症（1）足以导致高血压，并且（2）加剧与环孢菌素A肾毒性或外科手术5/6肾上腺素术相关的进行性肾脏损伤。在动物模型中，这些过程中涉及的机制包括尿酸介导的环氧合酶-II的激活，肾素血管紧张素系统的激活以及肾氮合酶的下降调节。如果可以将这些动物研究推广到人类人群，则对轻度高尿素血症的控制将为高血压治疗以及预防进行性肾脏疾病和心血管发病的新型治疗靶标提供新的方法。我们建议测试使用黄嘌呤氧化酶抑制剂别嘌呤醇（一种尿酸降低药物）是否将（1）儿童改善原发性高血压，（2）在接受环孢菌素或他心动杆菌的肾移植受者中控制高血压。我们将进一步研究高血压儿童中血清尿酸水平升高的生理机制，以及生化机制升高的血清尿酸导致血压升高。