The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension.
The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension.
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DOI：
10.1152/ajprenal.00040.2016
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发表时间：
2016-06
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通讯作者：
S. Weiss;A. Rosendahl;Daniel Czesla;C. Meyer-Schwesinger;R. Stahl;H. Ehmke;C. Kurts;P. Zipfel;J. Köhl;U. Wenzel
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作者：
S. Weiss;A. Rosendahl;Daniel Czesla;C. Meyer-Schwesinger;R. Stahl;H. Ehmke;C. Kurts;P. Zipfel;J. Köhl;U. Wenzel
适应性免疫反应和先天免疫反应导致高血压和高血压终末器官损害。在这里，我们确定了过敏毒素C5a在高血压终末器官损害中的作用。过敏毒素C5a是先天性免疫系统的一种主要炎症效应因子，在补体激活时产生。为此，我们评估了血管紧张素转换酶II诱导的肾和心脏损伤中C5a受体1(C5aR1)缺陷小鼠的表型。用绿色荧光蛋白(GFP)-C5aR1报告敲打小鼠检测C5aR1在浸润性和常驻肾细胞以及心肌细胞上的表达。从GFP-C5aR1报告小鼠肾脏分离的白细胞的流式细胞仪分析显示，28%的CD45阳性细胞表达C5aR1。树突状细胞是表达C5aR1的主要细胞群(88.5%)，其次是巨噬细胞和中性粒细胞。利用共聚焦显微镜，我们在肾脏中检测到C5aR1主要位于浸润性细胞上。在心脏中，仅有浸润性细胞染色C5aR1阳性。为了评价C5aR1缺乏在高血压损伤中的作用，我们采用了一种高血压加重模型。对34只野生型和32只C5aR1缺陷小鼠行单侧肾切除后给予Ang II(1.5 ng·g(-1)·min(-1))和生理盐水。C5aR1基因缺陷小鼠的肾脏损伤较小，蛋白尿显著减少。相比之下，注射血管紧张素II后，C5aR1基因缺陷小鼠的心脏损伤加速，心脏纤维化和心脏重量显著增加。未发现对血压有影响。总之，在实验性血管紧张素Ⅱ诱导的高血压中，C5a：C5aR1轴驱动肾脏的终末器官损害，但保护心脏纤维化和肥厚的发展。
Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.