Microcirculation in Renovascular Hypertension

描述（由申请人提供）：肾血管性高血压中的微循环肾动脉狭窄（RAS）正成为终末期肾病的更常见病因。尽管肾血运重建技术和支架置入术取得了进步，但狭窄的肾脏在成功干预后往往不会改善，甚至继续恶化，导致这些严重后果的机制尚未阐明。我们的研究表明，肾脏狭窄 12 周后出现明显的微血管损失和实质损伤，并伴有血管内皮生长因子 (VEGF) 的表达和可用性下降，血管内皮生长因子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，从而降低狭窄肾脏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果的潜力仍然未知。重要的是，我们的初步数据表明，RAS 可以通过激活 ET-A 受体来增加内皮素 (ET)-1，内皮素是一种有效的肾血管收缩剂和 VEGF 通路的下调剂。因此，该提议的总体假设是 RAS 导致 ET-1 介导的 VEGF 减少，导致肾微血管密度降低、肾功能下降和不可逆的肾损伤。此外，当前的提案将检验以下假设：通过保留肾内微脉管系统，血流动力学和狭窄肾脏响应血运重建（通过经皮腔内肾血管成形术）的功能将得到改善。我们开发了一种猪 RAS 模型，它非常模仿人类 RAS 患者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个肾的功能和结构。我们已经证明，快速计算机断层扫描 (CT) 可无创地表征体内肾脏体积、灌注、GFR、RBF 和肾小管动力学，以及内皮和上皮功能，而微型 CT 允许原位肾脏微循环的 3D 重建。因此，将在 RAS 进化过程中研究血运重建前后用 ET-A 受体阻滞剂或肾内 VEGF 治疗的猪 RAS 肾脏的功能和结构。相关性：将首次确定肾内微血管损伤在定义肾损伤进展和血运重建后缺血肾结局中的作用和机制。我们还将确定与不可逆性肾损伤相关的机制，以及肾损伤后缺血性肾功能可以保留或恢复的时间范围。这些研究将增进我们对肾缺血发病机制的理解，确定肾活力的损伤标志物和预测因子，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的常见疾病，会导致肾动脉主干直径变窄，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通阻塞的肾动脉以恢复流向肾脏的血液。然而，这种手术并不总是有效，一些患者仍然会出现肾脏疾病和高血压，这可能导致心脏病、中风和死亡。这项研究的目标是改进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。这些研究将极大地增进我们对肾动脉狭窄引起的肾损伤原因的理解，并有助于治疗这种疾病的患者。

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.