Role of Macrophage-Specific AT1R in Atherosclerosis of Chronic Kidney Dysfunction

巨噬细胞特异性 AT1R 在慢性肾功能不全动脉粥样硬化中的作用

基本信息

批准号：
8256798
负责人：
VALENTINA KON
金额：
$ 37.99万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-10 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256798
关键词：
Acceleration Angiotensin II Arterial Fatty Streak Atherosclerosis Blood Cells Blood Vessels Bone Marrow Cardiovascular Diseases Cause of Death Cell physiology Cells Cessation of life Chronic Chronic Kidney Failure Data Disease Progression Dyslipidemias Epidemiologic Studies Experimental Models Extracellular Matrix Foam Cells Functional disorder General Population Health Homeostasis In Vitro Infiltration Inflammation Inflammatory Injury Kidney Kidney Diseases Kidney Failure Link Lipids Macrophage Activation Medical Morbidity - disease rate Mus Outcome Pathogenesis Patients Peroxisome Proliferator-Activated Receptors Population Process Proteolysis Receptor, Angiotensin, Type 1 Renal Mass Role Study models Testing Therapeutic Vascular Diseases atherogenesis defined contribution high risk in vivo macrophage mortality novel receptor reconstitution research study

Acceleration Angiotensin II Arterial Fatty Streak Atherosclerosis Blood Cells Blood Vessels Bone Marrow Cardiovascular Diseases Cause of Death Cell physiology Cells Cessation of life Chronic Chronic Kidney Failure Data Disease Progression Dyslipidemias Epidemiologic Studies Experimental Models Extracellular Matrix Foam Cells Functional disorder General Population Health Homeostasis In Vitro Infiltration Inflammation Inflammatory Injury Kidney Kidney Diseases Kidney Failure Link Lipids Macrophage Activation Medical Morbidity - disease rate Mus Outcome Pathogenesis Patients Peroxisome Proliferator-Activated Receptors Population Process Proteolysis Receptor, Angiotensin, Type 1 Renal Mass Role Study models Testing Therapeutic Vascular Diseases atherogenesis defined contribution high risk in vivo macrophage mortality novel receptor reconstitution research study

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项目摘要

DESCRIPTION (provided by applicant): Although atherosclerotic cardiovascular disease (CVD) is 10-20-fold higher in patients with chronic kidney damage (CKD) than in the general population, our understanding of the underlying mechanisms remains very limited. Notably, CKD is an angiotensin II (AII)-responsive state where targeting AII actions constitutes the cornerstone of medical therapy for a whole range of progressive renal injuries. Atherosclerotic CVD has also been found to be AII responsive in epidemiological studies and experimental models. The proposed studies will evaluate the pathophysiologic and therapeutic implications of interactions between renal dysfunction and AII in promoting atherosclerosis, testing the hypothesis that the macrophage AII type 1 receptor (AT1R) channels proatherogenic mechanisms in this setting. We will use atherosclerosis-prone mice and induce early or moderate CKD. We will use mice deficient in AT1R as bone marrow donors to create chimeric mice with AT1R-deficient infiltrating cells, but intact AT1R on resident vascular cells. We can then evaluate mechanisms of AII effects on macrophages, vascular cells and matrix interactions in the setting of CKD. Our central hypothesis will be tested by the following Specific Aims: I. Define the contribution and mechanisms by which the macrophage AT1R modulates cellular processes involved in CKD-induced acceleration of atherosclerosis. We hypothesize that macrophage AT1R promotes CKD-induced atherogenesis by increasing macrophage infiltration, inflammation, foam cell formation and proteolysis of extracellular matrix. II. Determine the role of modulators of the proatherogenic effects of macrophage AT1R in CKD-induced acceleration of atherosclerosis. We hypothesize that macrophage AT1R activates not only proatherogenic processes but also counterbalancing factors, including macrophage PPAR, which moderate the net vasculopathy. PUBLIC HEALTH RELEVANCE These studies will further our understanding of the leading cause of death and illness in patients with kidney disease, namely, atherosclerosis. The magnitude of the problem, especially in early kidney damage, has only recently been appreciated and is currently understudied. The proposed experiments will examine how the macrophage, a key inflammatory blood cell, makes the atherosclerosis worse in this setting and may give ideas for better treatment.

描述（由申请人提供）：尽管慢性肾脏损伤（CKD）患者的动脉粥样硬化心血管疾病（CVD）比一般人群高10-20倍，但我们对基本机制的理解仍然非常有限。值得注意的是，CKD是一种血管紧张素II（AII）响应状态，在该状态下，针对AII作用的靶向AII构成了医疗治疗的基石，用于整个进行性肾脏损伤。在流行病学研究和实验模型中，还发现动脉粥样硬化CVD具有AII反应。拟议的研究将评估肾功能障碍与AII之间相互作用在促进动脉粥样硬化方面的相互作用的病理生理和治疗意义，并检验了在这种情况下巨噬细胞AII型1受体（AT1R）通道的假说。我们将使用容易动脉粥样硬化的小鼠，并诱导早期或中度的CKD。我们将使用缺乏AT1R的小鼠作为骨髓供体来创建具有AT1R缺陷式浸润细胞的嵌合小鼠，但在驻留的血管细胞上完好无损。然后，我们可以评估在CKD中对巨噬细胞，血管细胞和基质相互作用的AII效应的机制。我们的中心假设将通过以下特定目的测试：I。定义巨噬细胞AT1R调节与CKD诱导的动脉粥样硬化加速有关的细胞过程的贡献和机制。我们假设巨噬细胞AT1R通过增加巨噬细胞浸润，炎症，泡沫细胞形成和细胞外基质的蛋白水解来促进CKD诱导的动脉粥样硬化。 ii。确定巨噬细胞AT1R促进质源性作用的调节剂在CKD诱导的动脉粥样硬化加速度中的作用。我们假设巨噬细胞AT1R不仅激活了促进性的过程，还激活了包括巨噬细胞PPAR在内的平衡因素，巨噬细胞PPAR，它适应净血管病变。公共卫生相关性这些研究将进一步了解肾脏疾病患者的死亡和疾病主要原因，即动脉粥样硬化。该问题的大小，尤其是在早期肾脏损伤中，直到最近才受到赞赏，目前已经被研究了。拟议的实验将研究巨噬细胞是一种关键的炎性血细胞，使动脉粥样硬化在这种情况下更糟，并可能给予更好的治疗。