Oxidative Stress and Vascular Function in Chronic Kidney Disease

描述（由申请人提供）：内皮功能障碍被认为是慢性肾脏疾病（CKD）发生和进展的关键过程。此外，内皮功能障碍被认为是导致该人群心血管疾病风险增加的原因。内皮功能受损是动脉粥样硬化发展的主要事件，现在认识到CVD是CKD发病率和死亡率的最重要原因。了解CKD中内皮功能障碍的机制对于改善肾脏和心血管预后非常重要。CKD患者和血液透析（HD）患者的氧化应激升高，并有可能损害内皮功能。因此，继发于氧化应激的内皮功能障碍可能是CKD患者肾功能恶化和CVD风险增加的机制。对CKD中内皮功能障碍机制的研究有可能导致旨在维持肾功能和降低CKD心血管风险的治疗措施的发展。本研究的重点是阐明氧化应激是否在中重度CKD患者需要透析前的内皮功能障碍中起机制作用。本提案的第一个目标是通过急性输注抗坏血酸来研究氧化应激是否在CKD进展早期损害内皮功能中起机制作用。我们将使用抗坏血酸输注和内皮依赖性血流介导扩张（FMD）的测量来回答这个问题。我们假设CKD患者的FMD比健康对照者低，但在输注抗坏血酸后会得到改善。我们的第二个目标是确定生物标志物，预测单个患者对抗坏血酸输注的内皮反应，以便确定可能需要更积极干预以减少氧化应激的患者。我们假设氧化低密度脂蛋白、8-异前列腺素F2、髓过氧化物酶和不对称二甲基精氨酸可以预测CKD患者血管对抗坏血酸输注的反应程度。这些研究的创新之处在于，我们提出的抗坏血酸输注方案将为氧化应激在CKD中损害内皮功能中的作用提供新的信息。本项目旨在探讨慢性肾脏疾病血管功能障碍的机制，以便更好地了解导致肾脏疾病进展和心血管疾病发展的因素。了解这些机制可能有助于评估旨在改善慢性肾脏疾病血管功能的治疗方法。

DESCRIPTION (provided by applicant): Endothelial dysfunction is recognized as a key process in the development and progression of chronic kidney disease (CKD). Additionally, endothelial dysfunction is thought to contribute to the increased risk for CVD in this population. Impaired endothelial function is a primary event in the development of atherosclerosis and it is now recognized that that CVD is the most important cause of morbidity and mortality in CKD. An understanding of the mechanisms responsible for endothelial dysfunction in CKD is important for improving renal and cardiovascular outcomes. Oxidative stress is elevated in patients with CKD and those on hemodialysis (HD) and has the potential to impair endothelial function. Thus, endothelial dysfunction secondary to oxidative stress may be a mechanism by which renal function deteriorates and CVD risk increases in CKD. Investigations into the mechanism(s) of endothelial dysfunction in CKD have the potential to lead to development of therapeutic measures aimed at maintaining renal function and reducing cardiovascular risk in CKD. The focus of this proposal is to elucidate whether oxidative stress plays a mechanistic role in endothelial dysfunction in patients with moderate to severe CKD before they require dialysis. The first goal of this proposal is to investigate whether oxidative stress plays a mechanistic role in impairing endothelial function early in the progression of CKD by using an acute infusion of ascorbic acid. We will use an infusion of ascorbic acid and measurement of endothelial dependent flow mediated dilation (FMD) to answer this question. We hypothesize that FMD will be lower in CKD patients compared to healthy control subjects but will be improved during infusion of ascorbic acid. Our second goal is to identify biological markers that predict an individual patient's endothelial response to ascorbic acid infusion in order to identify patients who may require more aggressive intervention to reduce oxidative stress. We hypothesize that oxidized low density lipoproteins, 8-isoprostane F2 , myeloperoxidase, and asymmetric a dimethylarginine will predict the magnitude of vascular response to ascorbic acid infusion in CKD. These studies are innovative in that our proposed ascorbic acid infusion protocol will generate new information regarding the role of oxidative stress in impairing endothelial function in CKD. The purpose of this project is to investigate the mechanisms of vascular dysfunction in chronic kidney disease in order to better understand the facors that lead to a progression of renal disease and the development of cardiovascular disease. Understanding these mechanisms may aid in the evaluation of therapies aimed at improving vascular function in chronic kidney disease.