Distinct roles for C3a and C5a in complement-induced tubulointerstitial injury
Distinct roles for C3a and C5a in complement-induced tubulointerstitial injury
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DOI：
10.1038/ki.2011.158
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发表时间：
2011-09-01
影响因子：
19.6
通讯作者：
Quigg, Richard J.
中科院分区：
文献类型：
--
作者：
Bao, Lihua;Wang, Ying;Quigg, Richard J.
为了防止对宿主组织的损伤，补体激活受许多血浆和膜相关蛋白的调节，其中大多数限制C3和C5的激活。来自同基因宿主的循环C3流入缺乏Crry（一种降低C3转化酶活性的膜蛋白）的供体肾脏，引起自发补体激活，主要在小管间质，导致肾功能衰竭。为了确定C3a和C5a过敏毒素在小管间质炎症和纤维化中的作用，将Crry(-/-)C3（-/-）小鼠的肾脏移植到缺乏C3a和/或C5a受体的宿主中。尽管小管中补体的无限制激活不受受体状态的影响，但受体C3a受体缺乏导致肾白细胞浸润和小管间质炎症和纤维化程度显著降低，所有这些都导致肾功能保留。受体中C5a受体的缺失不仅无关紧要，而且C3a受体缺乏的保护作用也被消除，提示C3a和C5a受体信号在该模型中具有不同的作用。小管间质明显浸润，沿损伤小管有7/4(+)F4/80(+)CD11b（+）骨髓单核细胞和Thy1.2(+) T细胞，间质有I、III型胶原沉积，均为C3a受体依赖性。因此，阻断C3a受体信号是一种可能的治疗方法，可以减少肾脏炎症，并保持与补体激活相关的肾功能。肾脏国际（2011）80,524 -534；doi: 10.1038 / ki.2011.158;2011年6月15日在线发布
To prevent injury to host tissues, complement activation is regulated by a number of plasma and membrane-associated proteins, most of which limit C3 and C5 activation. An influx of circulating C3 from a syngeneic host into donor kidneys deficient in Crry (a membrane protein that reduces C3 convertase activity) causes spontaneous complement activation, primarily in the tubulointerstitum, leading to renal failure. To determine the roles of the C3a and C5a anaphylatoxins in tubulointerstitial inflammation and fibrosis, kidneys from Crry(-/-)C3(-/-) mice were transplanted into hosts lacking the C3a and/or C5a receptor. While unrestricted complement activation in the tubules was not affected by receptor status in the transplant recipient, C3a receptor deficiency in the recipients led to significantly reduced renal leukocyte infiltration and the extent of tubulointerstitial inflammation and fibrosis, all of which led to preserved renal function. The absence of C5a receptors in recipients was not only inconsequential, but the protective effect of C3a receptor deficiency was also eliminated, suggesting distinct roles of C3a and C5a receptor signaling in this model. There was significant infiltration of the tubulointerstitum with 7/4(+)F4/80(+)CD11b(+) myelomonocytic cells and Thy1.2(+) T cells along injured tubules, and interstitial collagen I and III deposition, all of which were C3a receptor dependent. Thus, blockade of C3a receptor signaling is a possible treatment to reduce renal inflammation and preserve renal function associated with complement activation. Kidney International (2011) 80, 524-534; doi:10.1038/ki.2011.158; published online 15 June 2011