Mechanism of Dialysis Arteriovenous Fistula Dysfunction

透析动静脉内瘘功能障碍的机制

• 批准号: 8212677
• 负责人: KARL A. NATH
• 金额: $ 34.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-03 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212677
• 关键词: Adverse effects; Anabolism; Anastomosis - action; Applications Grants; Arteries; Arteriovenous fistula; Artificial Kidney; Attenuated; Bile Pigments; Biology; Blood; Blood Vessels; Blood flow; CCL2 gene; Carbon Monoxide; Chemicals; Chronic; Chronic Kidney Failure; Coagulation Process; Complement; Development; Dialysis patients; Dialysis procedure; Drug Industry; Enzymes; Exhibits; Failure; Fistula; Functional disorder; Funding; GTP Cyclohydrolase; Gene Proteins; Genes; Hemodialysis; Human; Hyperplasia; Injury; Isoenzymes; Lead; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; N,N-dimethylarginine; Outcome; Patients; Peripheral; Phenotype; Process; Protein Isoforms; Proteins; Publishing; RANTES; Rattus; Research; Resistance; Rest; Rodent; Role; Site; Superoxides; Surgical Anastomosis; System; Therapeutic; Thromboplastin; Thrombosis; Time; Transcription Factor AP-1; Up-Regulation; Upper Extremity; Vasodilation; Veins; Venous; Work; arterial remodeling; attenuation; base; cofactor; heme oxygenase-1; inhibitor/antagonist; monocyte chemoattractant protein 1 receptor; mortality; premature; prevent; protective effect; small molecule; success; tetrahydrobiopterin; transcription factor

DESCRIPTION (provided by applicant): Dysfunction of hemodialysis vascular access is the single most important contributor to the morbidity and mortality of patients on chronic hemodialysis. The outcome for even the most favored vascular access, the arteriovenous fistula (AVF), is dismal with up to 60% of AVFs never functioning, and increasing subsets of once functional AVFs eventually ceasing to do so. AVF failure largely reflects 3 processes: neointimal hyperplasia, impaired vasorelaxation and aberrant arterial remodeling, and thrombosis. This application seeks to continue the examination of the basis for AVF dysfunction and the exploration of relevant therapeutic strategies. In the completed cycle, we utilized peripheral, surgically-created rodent AVF models, demonstrating that these models recapitulate the essential features of functional human AVFs, including increased blood flow, and the critical features of failing human AVFs, including neointimal hyperplasia, thrombosis, and induction of vasculopathic genes. In these models, we demonstrate activation of proinflammatory transcription factors (NF-?B and AP-1), and the upregulation of maladaptive, vasculopathic genes (MCP-1) and adaptive, vasoprotective genes (eNOS and HO-1). Our proposed aims, resting and building on findings made in the concluded cycle, include the following. AIM I. Hypothesis: The NOS system determines adaptation and injury in the AVF. Examination. Using the rat AVF model, this aim will examine the role of specific NOS isoforms, and whether the NOS cofactor, BH4, and superoxide anion scavenging determine the phenotype of the AVF. These studies will be complemented by strategies employing mutant mice to examine the roles of specific NOS isoforms, GTP cyclohydrolase (the BH4-synthesizing enzyme), and endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). AIM II. Hypothesis: HO and its products protect against AVF failure. Examination: This aim will determine whether the premature AVF failure in HO-1-/- mice involves impaired arterial blood flow and vascular reactivity, increased NF-?B and AP-1 activation, and/or tissue factor-dependent thrombosis. This aim will determine the effects of HO products (carbon monoxide and bile pigments) on AVF pathobiology in HO-1+/+ mice, and whether these products can attenuate the premature failure of AVFs in HO-1-/- mice; the effect of HO induction in protecting the AVF will also be assessed. Finally, the potential protective effects in the AVF of HO-2, the constitutive HO isozyme, will be determined. AIM III. Hypothesis: Mediators upstream and downstream of MCP-1 contribute to AVF failure. Examination: This aim will examine the role of intermediates upstream of MCP-1 mRNA, namely, NF-?B and AP-1, and intermediates downstream of MCP-1 mRNA, specifically, MCP-1 protein and the MCP-1 receptor (CCR2). As our findings in the AVF suggest that MCP-1 may exert its adverse effects via RANTES (CCL5), the role of CCL5 in AVF failure will be examined using CCL5-/- mice and a CCL5 inhibitor. This application thus examines how 3 fundamentally important systems in vascular biology determine AVF success or failure, and may disclose therapeutic avenues for small molecules expected shortly from the pharmaceutical industry. PUBLIC HEALTH RELEVANCE: Patients with chronic kidney disease who are treated by chronic hemodialysis require a vascular access for hemodialysis. A vascular access allows blood to be removed from the patient, to be purified by the artificial kidney, and then returned to the patient. There are three types of vascular accesses and, overwhelmingly, the most preferred form of vascular access is the hemodialysis arteriovenous fistula. An arteriovenous fistula is created when an artery in one of the upper limbs is joined to a vein. The veins and arteries then undergo substantial enlargement with an accompanying marked elevation in blood flow. Such increased blood flow through the artery and vein of the vascular access allows the blood first to be removed from the patient, then purified by the artificial kidney, and then returned to the patient. However, more than half of these arteriovenous fistulas do not ever function and substantial numbers, with time, cease to work. This grant application studies the reasons why these blood vessels in the arteriovenous fistula either do not develop or do not function after initially doing so. The main mechanisms include failure of these blood vessels to develop and to enlarge, a special type of thickening of the blood vessel wall known as neointimal hyperplasia, and finally, clotting of these blood vessels. In the completed funding cycle, this application discovered that three different types of genes/proteins could determine either the success or failure of the arteriovenous fistula. We wish to further understand how success or failure of the arteriovenous fistula is determined by the three different types of genes/proteins. Such an understanding would likely lead to new ways of either preventing fistula failure or treating it when it occurs.

描述（由申请人提供）：血液透析血管通路功能障碍是慢性血液透析患者发病率和死亡率的最重要因素。即使是最受欢迎的血管通路，动静脉瘘（AVF）的结局也是令人沮丧的，高达60%的AVF从未发挥功能，并且越来越多的曾经发挥功能的AVF最终停止发挥功能。AVF失败主要反映3个过程：新生内膜增生、血管舒张受损和异常动脉重塑以及血栓形成。本申请旨在继续检查AVF功能障碍的基础和探索相关的治疗策略。在完成的周期中，我们利用外周、动物性创建的啮齿动物AVF模型，证明这些模型概括了功能性人类AVF的基本特征，包括血流量增加，以及失败的人类AVF的关键特征，包括新生内膜增生、血栓形成和诱导血管病变基因。在这些模型中，我们证明激活的促炎转录因子（NF-？B和AP-1），以及适应不良的血管病变基因（MCP-1）和适应性的血管保护基因（eNOS和HO-1）的上调。我们在已结束的周期中得出的结论的基础上提出的目标包括以下内容。AIM岛假设：NOS系统决定AVF的适应和损伤。考试使用大鼠AVF模型，这一目的将检查特定的NOS亚型的作用，以及NOS辅因子，BH 4和超氧阴离子清除是否决定了AVF的表型。这些研究将通过采用突变小鼠的策略来补充，以检查特定NOS亚型，GTP环化水解酶（BH 4合成酶）和内源性NOS抑制剂，不对称二甲基精氨酸（ADMA）的作用。AIM II.假设：HO及其产品可防止AVF故障。考核：这一目的将确定是否过早AVF失败HO-1-/-小鼠涉及受损的动脉血流和血管反应性，增加NF-？B和AP-1激活，和/或组织因子依赖性血栓形成。该目的将确定HO产品（一氧化碳和胆色素）对HO-1+/+小鼠AVF病理生物学的影响，以及这些产品是否可以减轻HO-1-/-小鼠AVF的过早衰竭;还将评估HO诱导在保护AVF方面的作用。最后，将确定HO-2（组成型HO同工酶）在AVF中的潜在保护作用。AIM III.假设：MCP-1的上游和下游介导物导致AVF失败。检查：这一目的将检查MCP-1 mRNA上游的中间体，即NF-？B和AP-1，以及MCP-1 mRNA下游的中间体，特别是MCP-1蛋白和MCP-1受体（CCR 2）。由于我们在AVF中的发现表明MCP-1可能通过RANTES（CCL 5）发挥其不良作用，因此将使用CCL 5-/-小鼠和CCL 5抑制剂检查CCL 5在AVF衰竭中的作用。因此，本申请研究了血管生物学中3个基本重要的系统如何决定AVF的成功或失败，并可能揭示制药行业不久将推出的小分子治疗途径。 公共卫生相关性：接受长期血液透析治疗的慢性肾病患者需要血管通路进行血液透析。血管通路允许血液从患者体内取出，由人工肾净化，然后返回患者体内。有三种类型的血管通路，并且绝大多数情况下，最优选的血管通路形式是血液透析动静脉瘘。当上肢的动脉与静脉相连时，就会形成动静脉瘘。然后静脉和动脉经历实质性的扩张，伴随着血流的显著升高。通过血管通路的动脉和静脉的这种增加的血流允许血液首先从患者体内取出，然后通过人工肾纯化，然后返回到患者体内。然而，这些动静脉瘘中有一半以上从未发挥作用，随着时间的推移，大量动静脉瘘停止工作。这项拨款申请研究了为什么动静脉瘘中的这些血管在最初这样做后不发育或不起作用的原因。主要机制包括这些血管不能发育和扩大，称为新生内膜增生的特殊类型的血管壁增厚，以及最终这些血管的凝血。在完成的资金周期中，该应用程序发现三种不同类型的基因/蛋白质可以决定动静脉瘘的成功或失败。我们希望进一步了解动静脉瘘的成功或失败是如何由三种不同类型的基因/蛋白质决定的。这样的理解可能会带来预防瘘管病失败或在瘘管病发生时治疗瘘管病的新方法。