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

描述(申请人提供)：尽管动脉粥样硬化性心血管疾病(CVD)在慢性肾损害(CKD)患者中的发病率是普通人群的10-20倍，但我们对其潜在机制的了解仍然非常有限。值得注意的是，CKD是一种血管紧张素II(AII)反应状态，靶向AII活动构成了一系列进行性肾损伤药物治疗的基石。在流行病学研究和实验模型中，动脉粥样硬化性心血管疾病也被发现是有反应的。这项拟议的研究将评估肾功能障碍和AII之间的相互作用在促进动脉粥样硬化方面的病理生理学和治疗意义，验证巨噬细胞AII 1型受体(AT1R)通道在这种情况下的前动脉粥样硬化机制的假设。我们将使用易患动脉粥样硬化的小鼠，并诱导早期或中度的CKD。我们将使用AT1R缺陷的小鼠作为骨髓捐赠者，创造AT1R缺陷的浸润性细胞，但常驻血管细胞上AT1R完整的嵌合体小鼠。然后，我们可以在CKD的背景下评估AII对巨噬细胞、血管细胞和基质相互作用的作用机制。我们的中心假设将通过以下具体目标来检验：1.确定巨噬细胞AT1R在CKD诱导的动脉粥样硬化加速过程中调节细胞过程的作用和机制。我们假设巨噬细胞AT1R通过增加巨噬细胞的浸润、炎症、泡沫细胞的形成和细胞外基质的蛋白分解来促进CKD诱导的动脉粥样硬化的形成。II.确定巨噬细胞AT1R促动脉粥样硬化作用的调节剂在CKD诱导的动脉粥样硬化加速中的作用。我们假设巨噬细胞AT1R不仅激活了动脉粥样硬化的形成过程，而且还激活了平衡因子，包括巨噬细胞PPAR，从而缓解了净血管病变。公共卫生相关性这些研究将进一步加深我们对肾病患者死亡和疾病的主要原因，即动脉粥样硬化的理解。这个问题的严重性，特别是早期的肾脏损害，直到最近才被认识到，目前还没有得到充分的研究。拟议中的实验将研究巨噬细胞，一种关键的炎性血细胞，如何在这种情况下加剧动脉粥样硬化，并可能为更好的治疗提供想法。

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.