Role of Uric Acid in Cardiovascular and Renal Disease

尿酸在心血管和肾脏疾病中的作用

• 批准号: 8056089
• 负责人: Richard Joseph Johnson
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056089
• 关键词: Accounting; Adipocytes; Animal Model; Biological Availability; Blood; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cell Culture Techniques; Cells; Clinical Trials; Coupled; Development; Diabetes Mellitus; Dietary Practices; Energy Intake; Epidemic; Fructose; Funding; Goals; Human; Hypertension; Hyperuricemia; Inflammation; Insulin Resistance; Intake; Kidney Diseases; Lead; Light; Link; Lipids; Metabolic syndrome; Modeling; Nitric Oxide; Obesity; Overweight; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Process; Publishing; Rattus; Renin-Angiotensin System; Risk Factors; Role; Secondary to; Serum; Smooth Muscle Myocytes; Sweetening Agents; Syndrome; System; Testing; Uncertainty; United States National Institutes of Health; Uric Acid; Vascular Diseases; authority; base; cardiovascular disorder therapy; insight; novel strategies; prevent; sugar

DESCRIPTION (provided by applicant): Role of Uric Acid in Cardiovascular and Renal Disease We are currently having an epidemic of obesity, with two-thirds of the US population either overweight or frankly obese. Twenty-seven percent of our population have the metabolic syndrome, a known prediabetic condition, and 7% have diabetes. It is critical that we identify potential mechanisms to account for this great epidemic. While there are no doubt multiple causes, including excessive caloric intake and physical inactivity, we have identified another possible mechanism. Specifically, fructose, present in certain sweeteners and sugar, can rapidly induce metabolic syndrome in rats and has also been epidemiologically linked with the rise in obesity. Fructose is unlike all other sugars in that it raises uric acid rapidly in the blood. During the previous RO-1 we have found that uric acid has multiple effects on blood pressure, vascular disease, kidney disease and inflammation, and in particular we have found that uric acid can reduce nitric oxide release from vascular cells. We have further shown that fructose, by way of increasing uric acid, can cause obesity, insulin resistance and lipid abnormalities in rats, and that this can be partially prevented by lowering uric acid. In this application we will further investigate the mechanism by which uric acid contributes to this syndrome, and also dissect how fructose activates this pathway that leads to obesity and the metabolic syndrome. Studies will include determining the critical features about fructose that are necessary to induce the syndrome, with an emphasis on the type of fructose and its role in hypertension. We will also investigate how the rise in uric acid secondary to fructose causes features of the syndrome, with an emphasis on how fructose and uric acid disturb the normal vasculature, converting it from a noninflamed and dilated system to one that is inflamed and constricted. Finally, we will explore the possibility that fructose and uric acid may have direct effects on fat cells. Understanding the pathways by which uric acid, and fructose, can cause metabolic syndrome may give new insights into the pathogenesis of the obesity epidemic, with its impact on cardiovascular and kidney disease. Project Narrative: This study looks at the role of uric acid and fructose in the development of metabolic syndrome. The role of these factors in this syndrome, have not been widely studied. Identifying a casual role for these factors could lead to new treatments for metabolic syndrome.

描述（由申请人提供）：尿酸在心血管和肾脏疾病中的作用我们目前患有肥胖症流行，其中三分之二的人口超重或坦率地肥胖。我们27％的人口患有代谢综合征，一种已知的糖尿病疾病，有7％的人患有糖尿病。至关重要的是，我们确定潜在的机制来解释这种伟大的流行病。尽管毫无疑问，包括过量的热量摄入和身体不活跃，但我们已经确定了另一种可能的机制。具体而言，存在于某些甜味剂和糖中的果糖可以迅速诱导大鼠代谢综合征，并且在流行病学上也与肥胖症的升高联系在一起。果糖与所有其他糖不同，因为它会迅速在血液中添加尿酸。在上一个RO-1期间，我们发现尿酸对血压，血管疾病，肾脏疾病和炎症有多种影响，尤其是我们发现尿酸可以减少从血管细胞中释放一氧化氮。我们进一步表明，果糖通过增加尿酸会导致大鼠肥胖，胰岛素抵抗和脂质异常，并且可以通过降低尿酸来部分预防。在此应用中，我们将进一步研究尿酸对该综合征贡献的机制，并剖析果糖如何激活这种导致肥胖症和代谢综合征的途径。研究将包括确定诱导综合征所必需的果糖的关键特征，重点是果糖的类型及其在高血压中的作用。我们还将研究继发于果糖的尿酸的升高如何引起综合征的特征，重点是果糖和尿酸如何干扰正常的脉管系统，将其从非炎和扩张的系统转化为发炎和约束的系统。最后，我们将探索果糖和尿酸可能对脂肪细胞产生直接影响的可能性。了解尿酸和果糖会引起代谢综合征的途径可能会给肥胖症流行病的发病机理提供新的见解，并影响其对心血管和肾脏疾病的影响。 项目叙述：这项研究着眼于尿酸和果糖在代谢综合征发展中的作用。这些因素在该综合征中的作用尚未得到广泛研究。确定这些因素的随意作用可能会导致代谢综合征的新治疗方法。

项目成果

Attention-deficit/hyperactivity disorder: is it time to reappraise the role of sugar consumption?

• DOI: 10.3810/pgm.2011.09.2458
• 发表时间: 2011-09
• 期刊: Postgraduate medicine
• 影响因子: 4.2
• 作者: Johnson RJ;Gold MS;Johnson DR;Ishimoto T;Lanaspa MA;Zahniser NR;Avena NM
• 通讯作者: Avena NM

Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations.

• DOI: 10.1016/j.semnephrol.2011.08.002
• 发表时间: 2011-09
• 期刊: SEMINARS IN NEPHROLOGY
• 影响因子: 3.3
• 作者: Johnson, Richard J.;Lanaspa, Miguel A.;Gaucher, Eric A.
• 通讯作者: Gaucher, Eric A.

Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations.

• DOI: 10.1159/000345509
• 发表时间: 2012
• 期刊: Nephron. Experimental nephrology
• 作者: Sánchez-Lozada LG;Lanaspa MA;Cristóbal-García M;García-Arroyo F;Soto V;Cruz-Robles D;Nakagawa T;Yu MA;Kang DH;Johnson RJ
• 通讯作者: Johnson RJ

Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver.

• DOI: 10.1371/journal.pone.0048801
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lanaspa MA;Cicerchi C;Garcia G;Li N;Roncal-Jimenez CA;Rivard CJ;Hunter B;Andrés-Hernando A;Ishimoto T;Sánchez-Lozada LG;Thomas J;Hodges RS;Mant CT;Johnson RJ
• 通讯作者: Johnson RJ

A sensitive and specific liquid chromatography-tandem mass spectrometry method for the determination of intracellular and extracellular uric acid.

• DOI: 10.1016/j.jchromb.2009.05.037
• 发表时间: 2009-07-15
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Kim KM;Henderson GN;Ouyang X;Frye RF;Sautin YY;Feig DI;Johnson RJ
• 通讯作者: Johnson RJ