Microcirculation in Renovascular Hypertension

描述（由申请人提供）：肾血管性高血压的微循环肾动脉狭窄（RAS）正在成为终末期肾病的一种更常见的病因。尽管肾血管重建技术和支架植入术取得了进展，但狭窄的肾脏在成功的干预后往往没有改善，甚至继续恶化，导致这些严重后果的机制尚未阐明。我们已经表明，狭窄12周后的肾脏具有显著的微血管损失和实质损伤，伴随着血管内皮生长因子（VEGF）的表达和可用性降低，VEGF是血管生成的关键生理和病理介质。与急性缺血不同，肾血流量（RBF）的慢性减少可能无法维持VEGF的产生，从而可能降低狭窄肾中的肾微血管密度和灌注，并导致进行性和不可逆的肾损伤。然而，微血管损伤和损失在狭窄肾脏恶化中的作用以及通过保护肾脏微循环改善结局的潜力仍然未知。重要的是，我们的初步数据表明，RAS增加内皮素（ET）-1，一种有效的肾血管收缩剂和VEGF途径的下调剂，通过激活ET-A受体。因此，该提议的总体假设是RAS导致ET-1介导的VEGF降低，导致肾微血管密度降低、肾功能降低和不可逆的肾损伤。此外，目前的建议将测试的假设，即血流动力学和功能的狭窄的肾脏响应血运重建（经皮经腔肾血管成形术）将通过保留肾内微血管得到改善。我们已经开发了一种猪RAS模型，该模型密切模拟了RAS患者中发生的肾功能和结构变化，使我们能够使用强大的生理成像技术来表征单肾功能和结构。我们已经表明，快速计算机断层扫描（CT）的特点是非侵入性的在体内肾体积，灌注，GFR，RBF和肾小管动力学，以及内皮和上皮功能，而微CT允许在原位的肾微循环的3D重建。因此，在RAS的演变过程中，将研究血管重建前后用ET-A受体阻断剂或肾内VEGF治疗的猪RAS肾的功能和结构。相关性：肾内微血管损伤的作用和机制，在定义肾损伤的进展和缺血肾血运重建后的结果将首次确定。我们还将确定与不可逆肾损伤相关的机制，以及在确定的肾损伤后缺血肾功能可以保留或恢复的时间范围。这些研究将促进我们对肾缺血发病机制的理解，将确定损伤标志物和肾活力的预测因子，并为肾血管疾病患者提供可行的治疗方案。 公共卫生相关性：肾动脉狭窄是老年人常见的疾病，它会导致主肾动脉直径变窄，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尝试打开阻塞的肾动脉，以恢复血液流向肾脏。然而，这种方法并不总是有效的，一些患者仍然会继续发展肾脏疾病和高血压，这可能导致心脏病发作，中风和死亡。这项研究的目的是改善目前用于治疗这种疾病的疗法。我们相信，通过尝试刺激肾脏中额外血管的生长，我们可以改善肾动脉狭窄患者的肾功能。这些研究将极大地推进我们对肾动脉狭窄导致肾损害的原因的理解，并有助于这种疾病患者的管理。

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.