Microcirculation in Renovascular Hypertension

肾血管性高血压的微循环

• 批准号: 7885899
• 负责人: Alejandro Roberto Chade
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885899
• 关键词: Acute; Angioplasty; Animals; Architecture; Area; Atrophic; Attenuated; Biological Preservation; Blood Vessels; Blood flow; Caliber; Cessation of life; Chronic; Cicatrix; Data; Deterioration; Development; Disease; Distal; Elderly; End stage renal failure; Endothelin; Endothelin A Receptor; Endothelin-1; Epithelial; Etiology; Evolution; Family suidae; Fibrosis; Figs - dietary; Functional disorder; Glomerular Capillary; Glomerular Filtration Rate; Goals; Growth; Human; Hypertension; Image; Imaging Techniques; In Situ; Individual; Injury; Intervention; Investigation; Ischemia; Kidney; Kidney Diseases; Lead; Link; Maintenance; Measures; Mediating; Mediator of activation protein; Microcirculation; Modeling; Morbidity - disease rate; Morphology; Myocardial Infarction; Outcome; Pathogenesis; Pathway interactions; Patients; Perfusion; Physiological; Play; Procedures; Production; Regional Perfusion; Renal Artery Stenosis; Renal Blood Flow; Renal function; Renovascular Hypertension; Reporting; Research; Resolution; Role; Severities; Staging; Stenosis; Stimulus; Stroke; Structure; Techniques; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tubular formation; United States; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vasoconstrictor Agents; Work; X-Ray Computed Tomography; angiogenesis; base; clinically relevant; data modeling; density; design; glomerulosclerosis; hemodynamics; improved; in vivo; innovation; interstitial; kidney vascular structure; mortality; novel; public health relevance; reconstruction; renal artery; renal ischemia; research study; response; successful intervention; therapeutic target

DESCRIPTION (provided by applicant): Microcirculation in Renovascular Hypertension Renal artery stenosis (RAS) is becoming a more common etiology of end-stage renal disease. Despite the advances in renal revascularization techniques and stenting, the stenotic kidney often does not improve and even continues to deteriorate after a successful intervention, and the mechanisms leading to these grave outcomes have not been elucidated. We have shown that the kidney after 12 weeks of stenosis has marked microvascular loss and parenchymal damage, accompanied by decreased expression and availability of vascular endothelial growth factor (VEGF), a key physiological and pathological mediator of angiogenesis. Unlike acute ischemia, chronic reduction of renal blood flow (RBF) may fail to sustain VEGF production, which may thereby decrease renal microvascular density and perfusion in the stenotic kidney and lead to progressive and irreversible renal damage. Yet, the role that microvascular damage and loss has in deterioration of the stenotic kidney and the potential for improving the outcomes by protecting the renal microcirculation remain unknown. Importantly, our preliminary data show that RAS increases endothelin (ET)-1, a potent renal vasoconstrictor and down-regulator of the VEGF pathway through activation of the ET-A receptor. Thus, the overall hypothesis underlying this proposal is that RAS results in ET-1 mediated decreases in VEGF, leading to a decreased renal microvascular density, decreased renal function, and irreversible renal injury. Moreover, the current proposal will test the hypothesis that the hemodynamics and function of the stenotic kidney in response to revascularization (by percutaneous trasluminal renal angioplasty) will be improved by preserving the intrarenal microvasculature. We have developed a swine model of RAS that closely mimics the renal functional and structural changes that occur in humans with RAS, allowing us to use powerful physiological imaging techniques to characterize single-kidney function and structure. We have shown that fast computerized tomography (CT) characterizes non-invasively in vivo renal volume, perfusion, GFR, RBF and tubular dynamics, as well as endothelial and epithelial function, while micro-CT allows the 3D reconstruction of the renal microcirculation in situ. Thus, the function and structure of the swine RAS kidneys treated with ET-A receptor blockers or intra-renal VEGF, before and after revascularization, will be studied during the evolution of RAS. Relevance: The role and mechanisms of intra-renal microvascular injury in defining the progression of renal injury and the outcomes of the ischemic kidney after revascularization will be determined for the first time. We will also determine the mechanisms associated with irreversible renal injury, and the timeframe during which the function of the ischemic kidney could be preserved or restored after established renal injury. These studies will advance our understanding of the pathogenesis of renal ischemia, will identify injury markers and predictors of renal viability, and provide viable treatment options for patients with renovascular disease. PUBLIC HEALTH RELEVANCE: Renal artery stenosis, a frequent disease in older adults, produces a narrowing of the diameter of the main renal artery and may cause high blood pressure and renal disease. One approach to fix this condition is to try to open up the blocked renal artery to restore flow of blood to the kidney. However, this procedure is not always effective and some patients still go on to develop kidney disease and high blood pressure, which can lead to heart attacks, strokes, and death. The goal of this research is improve the current therapies used to treat this condition. We believe that by trying to stimulate the growth of additional blood vessels in the kidney that we can improve kidney function in individuals with renal artery stenosis. These studies will greatly advance our understanding of the causes of renal damage resulting from renal artery stenosis, and contribute towards management of patients with this condition.

描述（由申请人提供）：肾血管高血压肾动脉狭窄（RAS）的微循环正成为终末期肾脏疾病的病因。尽管肾脏血运重建技术和支架的进步取得了进步，但狭窄的肾脏通常不会改善，甚至在成功的干预后甚至继续恶化，导致这些严重结果的机制尚未得到阐明。我们已经表明，狭窄12周后的肾脏明显明显微血管丧失和实质性损害，并伴随着血管内皮生长因子（VEGF）的表达和可用性降低，这是血管生成的关键生理和病理介体。与急性缺血不同，肾脏血流（RBF）的慢性减少可能无法维持VEGF的产生，从而可以降低狭窄肾脏中肾脏微血管密度和灌注，并导致渐进且不可逆的肾脏损害。然而，微血管损伤和损失在狭窄肾脏恶化中具有的作用以及通过保护肾脏微循环来改善结果的潜力仍然未知。重要的是，我们的初步数据表明，通过激活ET-A受体的激活，RAS增加了内皮素（ET）-1，这是VEGF途径的有效肾脏血管收缩和下调剂。因此，该建议的总体假设是RAS导致ET-1介导的VEGF降低，导致肾脏微血管密度降低，肾功能降低和不可逆的肾损伤。此外，当前的建议将检验以下假设：狭窄肾脏的血流动力和功能是响应血运重建的（通过经皮腹骨肾血管成形术），可以通过保留肾内微腔的保留来改善。我们已经开发了一种RAS的猪模型，该模型紧密模仿了具有RAS的人类中发生的肾功能和结构变化，从而使我们能够使用强大的生理成像技术来表征单基尼的功能和结构。我们已经表明，快速计算机断层扫描（CT）表征了体内肾脏体积，灌注，GFR，RBF和管状动力学以及内皮和上皮功能的非侵入性，而Micro-CT则允许3D重建肾脏微循环原位。因此，在血运重建之前和之后，将在RAS的演化过程中研究接受ET-A受体阻滞剂或肾脏内VEGF处理的猪RAS肾脏的功能和结构。相关性：首次确定血运重建后肾脏微血管损伤在定义肾脏损伤进展和缺血性肾脏的结局中的作用和机制。我们还将确定与不可逆的肾脏损伤相关的机制，以及在确定的肾损伤后可以保留或恢复缺血性肾脏功能的时间范围。这些研究将提高我们对肾脏缺血发病机理的理解，确定肾脏生存力的损伤标志和预测因子，并为肾血管疾病患者提供可行的治疗选择。 公共卫生相关性：肾动脉狭窄是老年人常见疾病的肾动脉狭窄，会导致主要肾动脉直径狭窄，并可能导致高血压和肾脏疾病。解决这种情况的一种方法是试图打开阻塞的肾动脉，以恢复血液流向肾脏。但是，此过程并不总是有效的，有些患者仍然会发展肾脏疾病和高血压，这会导致心脏病发作，中风和死亡。这项研究的目的是改善用于治疗这种情况的当前疗法。我们认为，通过试图刺激肾脏中额外的血管的生长，我们可以改善肾动脉狭窄个体的肾脏功能。这些研究将大大提高我们对肾动脉狭窄导致肾脏损害的原因的理解，并有助于管理这种疾病的患者。