The role of dendritic cells and complement in arterial hypertension and hypertensive end organ damage

在过去的十年中，免疫系统在动脉性高血压发展中的重要性已经被认识到。树突状细胞是最重要的专业抗原呈递细胞，在动脉高血压中起着关键作用。树突状细胞影响血压和终末器官损伤的机制仍然知之甚少。树突状细胞表达一种功能活跃的矿皮质激素受体，并强烈表达过敏毒素受体C3aR、C5aR1和C5aR2。补体蛋白C3似乎也在动脉高血压中发挥作用。因此，我们在这个项目中有四个目标。矿糖皮质激素受体不仅作用于肾上皮细胞，也作用于非上皮细胞，在心血管疾病中起重要作用。我们的数据表明，在树突状细胞中选择性敲除矿皮质激素受体可降低血压并减少终末器官损伤。树突状细胞上的糖皮质激素受体的意义是什么？它是如何影响血压的？它在树突状细胞中对肾脏盐平衡的调节有什么作用？最近的研究表明，细胞内的C3具有代谢功能。使用C3敲除小鼠、选择性抑制肝脏C3的siRNA方法和树突状细胞中的C3敲除，我们将研究C3影响动脉高血压和树突状细胞中C3代谢作用的机制。我们的初步工作表明，过敏毒素受体缺乏在动脉高血压中具有不同的作用。通过报告小鼠和floxed敲除小鼠，我们将阐明过敏毒素受体在动脉高血压中的作用和相互作用。特别是，我们将在体内（包括RNA-seq）和体外研究这些受体对高血压树突状细胞的免疫和细胞生理作用。非典型溶血性尿毒症综合征是一种补体介导的疾病，与恶性肾硬化有临床和形态学上的重叠。后者是动脉高血压引起的最严重的肾损伤。我们对恶性肾硬化的人肾活检进行了形态学表征。利用补体定位和蛋白质组学方法，通过激光解剖显微镜从肾脏活检中获得组织，我们将研究补体系统异常是否导致恶性肾硬化。我们希望能够更好地了解树突状细胞在动脉高血压病理生理中的作用，并为动脉高血压和恶性肾硬化患者发现新的治疗靶点。

The importance of the immune system in the development of arterial hypertension has been recognized in the past decade. Dendritic cells, the most important professional antigen-presenting cells, play a key role in arterial hypertension. The mechanisms, how dendritic cells affect blood pressure and end organ damage, are still poorly understood. Dendritic cells express a functionally active mineralocorticoid receptor and show a strong expression of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2. The complement protein C3 also seems to play a role in arterial hypertension. Therefore, we have four goals in this project.1. The mineralocorticoid receptor plays an important role in cardiovascular diseases not only on renal epithelial cells but also on non-epithelial cells. Our data show that a selective knockout of the mineralocorticoid receptor in dendritic cells lowers blood pressure and reduces end organ damage. What is the significance of the mineralocorticoid receptor on dendritic cells and how does it affect blood pressure? What effects does it have in dendritic cells in the regulation of the salt balance in the kidney?2. Recent data show that intracellular C3 has metabolic functions. Using a C3 knockout mouse, a siRNA approach that selectively inhibits hepatic C3, and a C3 knockout in dendritic cells, we will examine the mechanisms by which C3 influences arterial hypertension and the metabolic effects of C3 in dendritic cells.3. Our preliminary work shows that deficiency of anaphylatoxin receptors has divergent effects in arterial hypertension. With the help of reporter and floxed knockout mice, we will elucidate the role and interactions of anaphylatoxin receptors among each other in arterial hypertension. In particular, we will investigate in vivo (including RNA-seq) and in vitro, which immunological and cell physiological effects the receptors have on dendritic cells in hypertension.4. Atypical hemolytic uremic syndrome is a complement-mediated disease that has clinical and morphological overlaps with malignant nephrosclerosis. The latter is the strongest kidney injury caused by arterial hypertension. We morphologically characterized human renal biopsies with malignant nephrosclerosis. Using complement mapping and a proteomic approach of tissue obtained by laser dissection microscopy from renal biopsies, we will investigate whether abnormalities in the complement system underlie the development of malignant nephrosclerosis.We expect to gain a much better understanding of the role of dendritic cells in the pathophysiology of arterial hypertension and to discover new therapeutic targets for patients with arterial hypertension and with malignant nephrosclerosis.