HDL and cardiovascular risk in chronic kidney disease

高密度脂蛋白和慢性肾脏病的心血管风险

• 批准号: 8877617
• 负责人: ANDREW N HOOFNAGLE
• 金额: $ 38.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877617
• 关键词: Activities of Daily Living; Adult; Aerobic Exercise; Affect; American; Americas; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Applications Grants; Atherosclerosis; Attenuated; Biological Assay; Biological Preservation; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell physiology; Cells; Cessation of life; Cholesterol; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Cohort Studies; Data; Development; Diet; Dietary Intervention; Disease Pathway; Disease Progression; End stage renal failure; Endothelial Cells; Endothelium; Event; Freedom; Functional disorder; Funding; Future; General Population; Glomerular Filtration Rate; Goals; Health; High Density Lipoproteins; High Prevalence; In Vitro; Individual; Inflammation; Intervention; Investigation; Kidney; Kidney Diseases; Kidney Failure; Laboratories; Lead; Low-Density Lipoproteins; Measures; Methods; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Nonesterified Fatty Acids; Outcome; Oxidative Stress; Pathway interactions; Patients; Persons; Phenotype; Population; Property; Proteins; Public Health; Randomized Controlled Trials; Renal function; Research Institute; Risk; Risk Factors; Staging; Stroke; United States; United States National Institutes of Health; Vasodilation; base; cardiovascular disorder risk; cardiovascular risk factor; design; diet and exercise; endothelial dysfunction; healthy lifestyle; high risk; improved; in vivo; inorganic phosphate; lifestyle intervention; macrophage; new therapeutic target; novel; particle; targeted treatment

DESCRIPTION (provided by applicant): Nearly one in every seven adults in America has chronic kidney disease (CKD), representing a 30% increase in the past decade. Individuals with advanced CKD are at extraordinarily high risk for loss of kidney function, cardiovascular events, and death, and cardiovascular disease is the leading cause of death in people with CKD. While much is unknown about why cardiovascular risk in individuals with CKD is so high, we and others have demonstrated that CKD is associated with increased systemic inflammation, elevated free fatty acids, and oxidative stress that lead to dysfunction of the endothelium. We and others have shown that high density lipoproteins (HDL) contain factors that reduce the level of activation and dysfunction of endothelial cells in vitro. Moreover, there is evidence that HDL from patients with CKD is altered in composition and function, which may directly cause endothelial dysfunction and lead to atherosclerosis and worsening kidney function. We have developed novel mass spectrometric methods to assess HDL composition and cell-based assays to assess the ability of HDL to preserve endothelial cell function. The combination of these assays provides for a comprehensive investigation of the molecules that contribute to HDL's anti-inflammatory capacity. Our overall hypothesis is that CKD causes changes to HDL composition and that these changes lead to increased endothelial dysfunction and greater risk of glomerular loss and cardiovascular disease (CVD). We also hypothesize that diet and exercise, an intervention that improves endothelial function in vivo, will lead to beneficial changes in HDL composition. Our goal is therefore to better understand the association of changes in HDL composition and function with endothelial dysfunction and clinical outcomes. We will take advantage of three well-characterized, NIH-funded clinical studies to elucidate the mechanisms behind HDL's ability to preserve endothelial cell function. To achieve these objectives, we propose the following aims: 1) Comprehensively characterize HDL composition and function in the CKD population; 2) Identify and quantify the changes in HDL composition and function that are associated with cardiac events, progression of kidney disease, and death; and 3) Determine whether healthy lifestyle interventions modify HDL composition and restore its anti-inflammatory properties in CKD subjects. This proposal will identify the molecular changes in HDL in subjects with CKD and how they are associated with endothelial dysfunction in vitro and in vivo. Moreover, our studies will identify the changes in HDL composition that are associated with cardiovascular and renal outcomes in a population at greatly increased risk of death.

描述(申请人提供)：在美国，近七分之一的成年人患有慢性肾脏疾病(CKD)，在过去十年中增加了30%。晚期CKD患者肾功能丧失、心血管事件和死亡的风险极高，心血管疾病是CKD患者的主要死亡原因。虽然CKD患者的心血管风险如此之高还不得而知，但我们和其他人已经证明，CKD与全身炎症增加、游离脂肪酸升高和导致内皮功能障碍的氧化应激有关。我们和其他人已经证明，高密度脂蛋白(HDL)包含在体外降低内皮细胞激活和功能障碍水平的因素。此外，有证据表明CKD患者的高密度脂蛋白在成分和功能上发生了改变，这可能直接导致内皮功能障碍，导致动脉粥样硬化和肾功能恶化。我们开发了新的质谱学方法来评估高密度脂蛋白的组成，并开发了基于细胞的分析来评估高密度脂蛋白保存内皮细胞功能的能力。这些检测的结合为全面研究与高密度脂蛋白抗炎能力有关的分子提供了基础。我们的总体假设是，慢性肾脏病引起高密度脂蛋白组成的变化，这些变化导致内皮功能障碍增加，肾小球丢失和心血管疾病(CVD)的风险增加。我们还假设，饮食和锻炼是一种改善体内内皮功能的干预措施，将导致高密度脂蛋白成分的有益变化。因此，我们的目标是更好地了解高密度脂蛋白组成和功能的变化与内皮功能障碍和临床结果的关系。我们将利用三项由NIH资助的、具有良好特征的临床研究来阐明高密度脂蛋白保护内皮细胞功能背后的机制。为了实现这些目标，我们提出了以下目标：1)全面描述CKD人群中的高密度脂蛋白的组成和功能；2)识别和量化与心脏事件、肾脏疾病进展和死亡相关的高密度脂蛋白的组成和功能的变化；以及3)确定健康的生活方式干预是否改变了CKD受试者的高密度脂蛋白的组成和恢复其抗炎特性。这项建议将确定慢性肾脏病患者高密度脂蛋白的分子变化，以及它们与体外和体内血管内皮细胞功能障碍的关系。此外，我们的研究将确定在死亡风险大大增加的人群中，高密度脂蛋白成分的变化与心血管和肾脏结果相关。