Mechanistic Role of CD4+ T-Cells in Atherosclerotic Renal Artery Stenosis

描述（由申请人提供）：动脉粥样硬化性肾动脉狭窄（ARAS）是一种肾动脉狭窄导致肾血流量减少并导致肾萎缩和高血压的疾病。ARAS是肾衰竭的主要原因。65岁以上人群中有超过7%的人存在这种情况，高达45%的冠状动脉疾病患者存在这种情况，高达17%的II型糖尿病和高血压患者存在这种情况。ARAS患者的最佳管理存在争议，因为血运重建术和/或药物治疗往往不能改善肾功能。目前的研究范式表明炎性M1巨噬细胞是ARAS肾损伤发展的免疫介质。然而，最近的研究表明，CD4+ T细胞激活并分化为炎性Th1 T细胞可能是导致狭窄肾中M1巨噬细胞募集和分化的初始事件。尽管T细胞和ARAS之间存在相关性，但在狭窄肾中，T细胞募集、激活和介导炎症、肾损伤和萎缩的机制尚不明确。这是拟议研究的重点。我们假设肾树突状细胞将Th1 T细胞不依赖抗原激活和募集到狭窄肾中，通过促进M1巨噬细胞分化介导损伤。为了验证这一假设，我们制定了三个具体目标。首先，我们将在小鼠肾动脉狭窄模型中确定肾树突状细胞对CD4+ T细胞募集是否必要。我们的假设预测，肾树突状细胞是必需的CD4+ T细胞募集到狭窄的肾脏。为了验证这一观点，我们将在缺乏树突状细胞的小鼠模型中诱导肾动脉狭窄，并确定缺乏树突状细胞是否会降低CD4+ T细胞的激活，从而保护狭窄的肾脏免受萎缩。其次，我们将研究在小鼠肾动脉狭窄模型中，抗原介导的T细胞激活对于CD4+ T细胞参与肾损伤是否必要。我们将在只含有非自体抗原特异性T细胞的转基因小鼠中诱导肾动脉狭窄，并确定缺乏自体抗原是否能保护狭窄的肾脏免于萎缩。

DESCRIPTION (provided by applicant): Atherosclerotic renal artery stenosis (ARAS) is a condition where narrowing of the renal artery decreases blood flow to the kidney and leads to development of renal atrophy and hypertension. ARAS is a major cause of renal failure. It is present in over 7% of individuals over 65 years, in up to 45% of patients with coronary artery disease, and in up to 17% of patients with both type II diabetes and hypertension. Optimal management of patients with ARAS is controversial as both revascularization and/or pharmaceutical treatment often fails to improve renal function. Current paradigms point to inflammatory M1 macrophages as the immune mediator in the development of renal injury in ARAS. However, recent studies suggest that CD4+ T cell activation and differentiation into inflammatory Th1 T cells might be the initial events that lead to M1 macrophage recruitment and differentiation in the stenotic kidney. Despite this correlation between T cells and ARAS, the mechanisms by which T cells are recruited, activated, and mediate development of inflammation, renal injury, and atrophy in the stenotic kidney are not well defined. This is the focus of the proposed studies. We hypothesize that the antigen-independent activation and recruitment of Th1 T cells into the stenotic kidney by renal dendritic cells mediates injury by promoting M1 macrophage differentiation. To test this hypothesis, we develop three specific aims. First, we will determine if renal dendritic cells are necessary for CD4+ T cell recruitment after renal artery stenosis in a mouse model. Our hypothesis predicts that renal dendritic cells are necessary for CD4+ T cell recruitment to the stenotic kidney. To test this idea, we will induce renal artery stenosis in a mouse model lacking dendritic cells and determine if lack of dendritic cells reduces CD4+ T cell activation and thereby protects the stenotic kidney from atrophy. Second, we will address whether antigen-mediated T cell activation is necessary for CD4+ T cell participation in kidney damage after renal artery stenosis in a mouse model. We will induce renal artery stenosis in a transgenic mouse containing only T cells that are specific for a non-self- antigen, and determine if lack of self-antigen protects the stenotic kidney from atrophy. Third, we will determine if Th1 T cells mediate the development of renal injury by promoting M1 macrophage differentiation after renal artery stenosis in mice models. To test this idea, we will induce renal artery stenosis in mice with T cells that are unable to differentiate into Th1 cells and in mice with macrophages that are unable to differentiate into M1 macrophages. The proposed studies will identify immune responses that could be targeted for effective treatment. Thus, the results of these studies will lead to a better understanding of the mechanistic role of CD4+ T cells in the pathophysiology of ARAS, and could potentially lead to development of novel therapy for treatment of this disease.