Microcirculation in Renovascular Hypertension

描述(申请人提供)：肾血管性高血压的微循环肾动脉狭窄(RAS)正成为终末期肾脏疾病的一种更常见的病因。尽管肾血管重建术和支架置入术取得了进展，但狭窄的肾脏在成功介入治疗后往往没有改善，甚至继续恶化，导致这些严重后果的机制尚未阐明。我们发现，狭窄12周后的肾脏有明显的微血管丢失和实质损伤，并伴随着血管生成的关键生理和病理介质-血管内皮生长因子(VEGF)的表达和可获得性降低。与急性缺血不同，慢性肾血流量减少可能无法维持血管内皮生长因子的产生，从而降低狭窄肾脏的微血管密度和灌注量，导致进展性和不可逆性肾损伤。然而，微血管损伤和丢失在狭窄肾脏恶化中的作用以及通过保护肾脏微循环来改善预后的可能性仍不清楚。重要的是，我们的初步数据显示，RAS通过激活ET-A受体增加了内皮素(ET)-1，这是一种有效的肾脏血管收缩因子和血管内皮生长因子途径的下调因子。因此，支持这一建议的总体假设是RAS导致ET-1介导的血管内皮生长因子减少，导致肾微血管密度降低，肾功能下降，以及不可逆转的肾损伤。此外，目前的建议将检验这样一种假设，即通过保留肾内微血管，狭窄肾脏的血流动力学和功能在血运重建(通过经皮腔内肾血管成形术)后将得到改善。我们已经开发了一种猪RAS模型，该模型可以非常接近地模拟RAS患者的肾脏功能和结构变化，使我们能够使用强大的生理成像技术来表征单个肾脏的功能和结构。我们已经证明，快速计算机断层扫描(CT)可以无创地表征活体肾脏的体积、灌注量、GFR、RBF和肾小管动力学，以及内皮和上皮功能，而Micro-CT可以原位三维重建肾脏微循环。因此，在RAS的演变过程中，用ET-A受体阻滞剂或肾内注射血管内生长因子治疗的猪RAS肾脏的功能和结构将在RAS的演变过程中得到研究。相关性：将首次确定肾内微血管损伤在确定肾损伤的进展和血运重建后缺血肾脏的结局中的作用和机制。我们还将确定与不可逆肾损伤相关的机制，以及在已建立的肾损伤后，缺血肾脏的功能可以保留或恢复的时间框架。这些研究将促进我们对肾缺血发病机制的理解，将识别损伤标志物和肾脏存活的预测因素，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病，会导致主肾动脉管径变窄，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堵塞的肾动脉，以恢复肾脏的血液流动。然而，这一过程并不总是有效的，一些患者仍然会继续发展为肾脏疾病和高血压，这可能会导致心脏病发作、中风和死亡。这项研究的目的是改进目前用于治疗这种疾病的治疗方法。我们相信，通过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。这些研究将极大地促进我们对肾动脉狭窄导致肾损害的原因的理解，并有助于治疗这种情况的患者。

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.