Uric Acid in Childhood Hypertension

描述(由申请人提供)： 自19世纪70年代以来，高尿酸血症和高血压之间的联系一直被反复观察到。一般来说，这种联系被认为没有因果作用，因为有一种假设认为，血清尿酸的增加仅仅是肾小球滤过率降低的替代品。最近，这种联系被重新评估，因为几项大型临床试验的结果表明，高尿酸血症是心血管预后不良的独立危险因素。我们自己的数据显示，血尿酸与儿童原发性高血压密切相关。此外，使用大鼠轻度高尿酸血症模型进行的实验数据显示，高尿酸血症本身就足以导致高血压，(2)加剧与环孢素A肾毒性或外科5/6肾切除术相关的进行性肾脏损伤。在动物模型中，参与这些过程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和肾脏一氧化氮合酶的下调。如果这些动物研究可以推广到人类人群，控制轻度高尿酸血症将为高血压的管理提供新的方法，并为预防进行性肾脏疾病和心血管疾病的发病率提供新的治疗靶点。我们建议测试使用黄嘌呤氧化酶抑制剂别嘌醇，一种降低尿酸的药物，是否将(1)改善儿童的原发性高血压，(2)控制接受环孢素或他克莫司的肾移植受者的高血压。我们将进一步探讨高血压儿童血尿酸水平升高的生理机制，以及血尿酸升高导致血压升高的生化机制。

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.