Tissue Oxygenation in Human Renovascular Hypertension

慢性肾脏疾病（CKD）在美国正在增加，尤其是老年人。超过八 在美国，有100万人的肾功能下降。即使是轻微程度的慢性肾脏病归因于高- 紧张和糖尿病预示着主要的心血管风险，包括心肌梗死死亡。两 这些病症的特征在于肾内的小血管疾病。大肾动脉粥样硬化 血管疾病可加速高血压，叠加在小血管疾病上并产生肾损伤。 肾血管疾病既激活氧化途径又产生纤维化。这些规则 对人类疾病的致病途径知之甚少。BOLD（血氧水平依赖）磁性 磁共振（MR）提供脱氧血红蛋白的直接、非侵入性测量。实验研究 表明BOLD MR水平与肾皮质和髓质内局部氧张力直接相关。 我们的初步研究结果表明，在阻断血管内皮细胞的过程中，通过BOLD MR测量的脱氧血红蛋白变化， 钠重吸收与动脉粥样硬化性肾血管病患者不可逆肾功能障碍水平相关 疾病在这些研究中要检验的总体假设是脱氧血红蛋白信号 (the BOLD磁共振方法学的基础），其反映了局部肾缺血，预测 动脉粥样硬化性血管疾病肾脏中氧化和纤维化途径的激活。我们提出 利用这些方法作为阐明发病机制和指导治疗的手段 动脉粥样硬化性肾血管疾病 我们的具体目标是研究年龄、种族和大血管性肾血管疾病的作用， 改变肾脏耗氧量的条件，以检查它们在调节损伤途径中的作用：目的 号1将检查与年龄和种族相关的小血管变化的作用，以确定髓和 速尿引起的BOLD MR皮质改变及其与局部血流量的关系（测量 通过多探测器CT）、氧化途径和纤维化生物标志物。目标2将研究一系列变化 在狭窄和非狭窄肾脏中， 改变血管内血运重建的耗氧量水平。目标3将检查序列 全身血压降低过程中狭窄和非狭窄肾脏局部BOLD MR的变化 使用抗高血压治疗而不进行肾血管重建。 这些项目将提供一个关键的延伸到人类从其他研究我们的计划项目 与肾血管性高血压和损伤机制（Romero）、微血管损伤和修复相关 （Lerman）和肾纤维化反应中的细胞信号传导途径（Grande）。

Chronic kidney disease (CKD) is increasing in the U.S., particularly in older individuals. More than eight million people in the US have reduced kidney function. Even minor degrees of CKD attributed to hyper- tension and diabetes predict major cardiovascular risks, including death from myocardial infarction. Both conditions are characterized by small vessel disease within the kidney. Atherosclerosis of the larger renal vessels can accelerate hypertension, is superimposed upon small vessel disease and produces renal injury. Renovascular disease both activates oxidative pathways and produces fibrosis. The regulation of these pathways in human disease is poorly understood. BOLD (Blood Oxygen Level Dependent) magnetic resonance (MR) provides a direct, non-invasive measure of deoxygenated hemoglobin. Experimental studies indicate that BOLD MR levels relate directly to regional oxygen tension within kidney cortex and medulla. Our preliminary results indicate that deoxyhemoglobin changes measured by BOLD MR during blockade of sodium reabsorption are related to levels of irreversible kidney dysfunction in atherosclerotic renovascular disease. The overall hypothesis to be examined in these studies is that deoxygenated hemoglobin signals (the basis for BOLD magnetic resonance methodology), which reflect regional kidney ischemia, predict activation of oxidative and fibrogenic pathways in kidneys with atherosclerotic vascular disease. We propose to utilize these methods as a means of elucidating the pathogenesis and guiding therapy in human atherosclerotic renovascular disease. Our specific aims will examine the role of age, ethnicity and large-vessel renovascular disease under conditions that modify kidney oxygen consumption to examine their role in regulating injury pathways: Aim No. 1 will examine the role of small vessel changes related to age and ethnicity to determine medullary and cortical changes in BOLD MR induced by furosemide and their relationship to regional blood flow (measured by multi-detector CT), oxidative pathways and fibrogenic biomarkers. Aim No. 2 will examine serial changes in medullary and cortical BOLD MR induced by furosemide in stenotic and non-stenotic kidneys after changing levels of oxygen consumption with endovascular revascularization. Aim No. 3 will examine serial changes in regional BOLD MR in stenotic and non-stenotic kidneys during systemic blood pressure reduction using antihypertensive therapy without renalrevascularization. These projects will provide a critical extension into humans from the other studies of our program project related to mechanisms of renovascular hypertension and injury (Romero), microvascular injury and repair (Lerman) and pathways of cell signaling in renal fibrogenic responses (Grande).