Microvascular Function in Chronic Kidney Disease

项目摘要 内皮功能障碍被认为是慢性阻塞性肺疾病发生发展的关键过程 肾病(CKD)。此外，内皮功能障碍被认为是导致心脏病风险增加的原因之一 这一人群中的心血管疾病。血管内皮细胞功能受损是血管病变发生发展的主要事件 动脉粥样硬化，现已认识到心血管疾病(CVD)是 慢性肾脏病的发病率和死亡率。对内皮细胞发生机制的理解 慢性肾脏病的功能障碍对于改善肾脏和心血管预后很重要。氧化应激是 CKD患者和血液透析(HD)患者升高，并有可能损害血管内皮细胞 功能。因此，继发于氧化应激的内皮功能障碍可能是肾脏 CKD患者功能恶化，CVD风险增加。此外，不对称二甲基精氨酸(ADMA)， 一氧化氮合酶(NOS)内源性抑制物在慢性肾脏病中升高，可减少NO的产生 通过与L精氨酸争夺一氧化氮合酶。因此，竞争可能会导致L精氨酸的相对不足 阿霉素A与L精氨酸对内皮型一氧化氮合酶的影响血管内皮细胞的作用机制研究(S) 慢性肾脏病的功能障碍有可能导致旨在维持 肾功能和降低心血管风险。大多数关于肾脏疾病的内皮功能的研究都有 已在终末期肾脏疾病中实施，并侧重于大循环。我们建议 在需要透析前研究中重度慢性肾脏病患者的内皮功能。 此外，我们建议通过以下方法研究降低微循环NO生物活性的机制 应用激光多普勒血流测定仪评价局部加热对皮肤血管扩张的影响 皮内微透析。微血管功能受损是一个全身性过程，因此皮肤提供了 可访问的微血管系统研究场所。对皮肤局部加热的充血反应 导致轴突反射介导的初始峰值和依赖NO和NO的持续平台 为研究微血管内皮细胞功能提供了有价值的工具。这项研究的目的是1) 确定氧化应激在减少一氧化氮介导的皮肤损伤中是否起机制作用 中到重度慢性肾脏病患者局部加热后的血管扩张反应和2)确定 L精氨酸相对缺乏导致患者一氧化氮介导的皮肤血管扩张功能降低 伴有中到重度的慢性肾脏病。这些研究具有创新性，因为它们将产生新的信息 关于CKD患者微循环中NO生物活性受损的机制。因此， 该项目的成功完成预计将在#年产生潜在的重要影响。 扩大我们对CKD患者内皮功能障碍的理解，这可能会导致设计出 在这一人群中维持肾功能并降低心血管风险。叙述性 本课题的目的是探讨慢性肾脏血管功能障碍的发病机制。 以更好地了解导致肾脏疾病进展的因素和 心血管疾病的发展。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。

Project Summary 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 cardiovascular disease (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. Additionally, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is elevated in CKD and can reduce NO production by competing with L-arginine for NOS. Thus, a relative deficit in L-arginine may result from the competition between ADMA and L-arginine for endothelial NOS. 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. Most studies of endothelial function in renal disease have been performed in end stage renal disease and have focused on the macrocirculation. We propose to study endothelial function in patients with moderate to severe CKD before they require dialysis. Additionally, we propose to study the mechanisms of reduced NO bioactivity of the microcirculation by assessing cutaneous vasodilation in response to local heating by using laser Doppler flowmetry and intradermal microdialysis. Impaired microvascular function is a systemic process thus the skin provides an accessible site for the study of the microvasculature. The hyperemic response to local heating of the skin results in an initial peak that is axon-reflex mediated and a sustained plateau that is dependent on NO and provides a valuable tool for studying microvascular endothelial function. The aims of this study are 1) To determine if oxidative stress plays a mechanistic role in reducing nitric oxide-mediated cutaneous vasodilation in response to local heating in patients with moderate to severe CKD and 2) To determine if a relative deficit of L-arginine contributes to reduced nitric-oxide mediated cutaneous vasodilation in patients with moderate to severe CKD. These studies are innovative in that they will generate new information regarding the mechanisms of impaired NO bioactivity in the microcirculation of CKD patients. Therefore, the successful completion of this project would be expected to have a potentially important impact by expanding our understanding of endothelial dysfunction in CKD which may lead to therapies designed to maintain renal function and reduce cardiovascular risk in this population. Narrative The purpose of this project is to investigate the mechanisms of vascular dysfunction in chronic kidney disease in order to better understand the factors 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.