Irreversible Kidney Injury in Renovascular Hypertension

描述(由申请人提供)： 肾血管性高血压(RVH)和肾血管疾病的诊断、评估和治疗一直是激烈争论的主题。肾血管重建术的临床试验表明，血压控制和/或肾功能恢复的显著改善很难实现或可靠地预测，部分原因是导致肾损伤和RVH不可逆转的因素仍不清楚。缺乏合适的模型和工具来评估狭窄肾的血流动力学和功能损害，或对侧肾脏的代偿反应，是推动这一领域发展的主要障碍。此外，对于介导不可逆的肾脏重塑、纤维化和RVH的机制和细胞内信号级联，以及并发动脉粥样硬化如何调节它们，我们知之甚少。PPG应用的总体目标是获得有关RVH和肾血管疾病的关键生理学知识，以促进该疾病的诊断和治疗。具体地说，我们将试图解决导致狭窄和对侧肾脏不可逆损伤的内在肾脏病理生理机制，从而限制许多患者进行血运重建以改善肾功能和血压的益处。我们的工作假设是，肾血管疾病和RVH激活了多条血流动力学紊乱、进行性肾脏损伤和纤维化的途径，这些途径受到氧化应激和缺血的调节。这些途径被对侧肾损伤和共存的动脉粥样硬化放大，并可能阻碍肾脏和血压的恢复。将在四个相互关联的项目中调查几个因素，这四个项目构成并促进了本项目小组的中心主题。该计划将在项目1中描述狭窄和对侧肾损伤对经皮肾血管成形术或猪RVH药物治疗反应的作用和影响，以及项目2中动脉粥样硬化对肾脏损伤演变的加剧作用。项目3将在转基因小鼠中探索时间进程和形态变化与细胞信号之间的相关性。虽然在动物模型中获得的知识与人类的相关性最终将在项目4中得到测试和确认。这些项目将应用新的生理成像工具来研究单个肾脏的血流动力学、功能和缺血，以及尖端分子生物学技术来表征肾脏损伤。并将应用它们来评估干预措施的潜力，包括肾脏血运重建、降压药物治疗或祖细胞以保护肾脏。使用研究区域循环及其与组织损伤的关系的新工具来识别和修改这些途径，将有助于识别高血压患者面临不可逆转的肾脏损伤的风险，以及那些最有可能从逆转这些途径的治疗干预中受益的人。

DESCRIPTION (provided by applicant): The diagnosis, evaluation, and treatment of renovascular hypertension (RVH) and renovascular disease continue to be a subject of intense debate. Clinical trials of renal revascularization indicate that significant improvement in blood pressure control and/or recovery of renal function are difficult to achieve or predict reliably, partly because the factors that render renal injury and RVH irreversible remain unclear. The lack of appropriate models and tools to assess the hemodynamic and functional impairment in the stenotic kidney, or the compensatory response of the contralateral kidney, is a major impediment to advancing this field. Furthermore, little is known about the mechanisms and intracellular signaling cascades that mediate irreversible renal remodeling, fibrosis, and RVH, and how they are modulated by concurrent atherosclerosis. The overall objective of this PPG application is to gain critical knowledge about the pathophysiology of RVH and renovascular disease that will advance the diagnosis and treatment of this disease. Specifically, we will attempt to resolve intrinsic renal pathophysiological mechanisms that lead to irreversible injury in the stenotic and contralateral kidneys, and thereby limit the benefits of revascularization to improve renal function and blood pressure in many patients. Our working hypothesis is that renovascular disease and RVH activate multiple pathways of hemodynamic perturbation, progressive renal injury, and fibrogenesis, which are modulated by oxidative stress and ischemia. These pathways are amplified by contralateral kidney injury and coexisting atherosclerosis, and can hinder renal and blood pressure recovery. Several factors will be investigated in the four interrelated projects that compose and contribute to the central theme of this PPG. The proposal will characterize the role and effect of stenotic and contra-lateral kidney damage on the response to percutaneous transluminal renal angioplasty or to medical treatment in swine RVH in Project 1. and the exacerbating effects of atherosclerosis on evolution of renal injury in Project 2. The time course and the correlation between morphologic alterations and cellular signaling will be explored in genetically modified mice in Project 3. while the relevance to humans of knowledge gained in animal models will ultimately be tested and confirmed in Project 4. These projects will apply novel physiological imaging tools to study singlekidney hemodynamics, function, and ischemia, and cutting edge molecular biology techniques to characterize renal injury, and will apply them to assess the potential of interventions including renal revascularization, antihypertensive drug therapy, or progenitor cells to preserve the kidney. Identification and modification of these pathways using novel tools to study regional circulation and its relationship to tissue injury will allow identification of hypertensive individuals at risk for irreversible kidney injury, and those most likely to benefit from therapeutic intervention to reverse those pathways.