The complement factor 5a receptor 1 has a pathogenic role in chronic inflammation and renal fibrosis in a murine model of chronic pyelonephritis.
The complement factor 5a receptor 1 has a pathogenic role in chronic inflammation and renal fibrosis in a murine model of chronic pyelonephritis.
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DOI：
10.1016/j.kint.2016.04.023
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发表时间：
2016-09
影响因子：
19.6
通讯作者：
Zhou W
中科院分区：
文献类型：
--
作者：
Choudhry N;Li K;Zhang T;Wu KY;Song Y;Farrar CA;Wang N;Liu CF;Peng Q;Wu W;Sacks SH;Zhou W
补体因子5a（C5 a）与其受体（C5 aR 1）的相互作用有助于炎症性疾病的发病机制，包括急性肾损伤。然而，它在慢性炎症中的作用，特别是在病原体相关疾病中，在很大程度上是未知的。在此，我们在慢性肾盂肾炎的小鼠模型中检测慢性炎症和肾纤维化的发展是否依赖于C5 aR 1。与C5 aR 1充足的小鼠相比，C5 aR 1缺陷（C5 aR 1-/-）小鼠在感染后肾脏中的细菌负荷、肾小管损伤和肾小管间质纤维化显著减少。这与C5 aR 1-/-小鼠感染后Ly 6Chi促炎单核细胞/巨噬细胞群体特异性肾白细胞浸润减少和关键促炎因子和促纤维化因子肾内基因表达减少相关。拮抗C5 aR 1可降低肾细菌负荷、组织炎症和肾小管间质纤维化。离体和体外研究表明，在感染条件下，C5 a/C5 aR 1相互作用上调肾小管上皮细胞和单核细胞/巨噬细胞产生促炎和促纤维化因子，而单核细胞/巨噬细胞的吞噬功能下调。因此，肾小管上皮的C5 aR 1依赖性细菌定殖、C5 a/C5 aR 1介导的对致尿路疾病大肠杆菌的局部炎症反应的上调和吞噬细胞的吞噬功能的损害有助于肾脏的持续细菌定殖、慢性肾脏炎症和随后的肾小管间质纤维化。
Complement factor 5a (C5a) interaction with its receptor (C5aR1) contributes to the pathogenesis of inflammatory diseases, including acute kidney injury. However, its role in chronic inflammation, particularly in pathogen-associated disorders, is largely unknown. Here we tested whether the development of chronic inflammation and renal fibrosis is dependent on C5aR1 in a murine model of chronic pyelonephritis. C5aR1-deficient (C5aR1-/-) mice showed a significant reduction in bacterial load, tubule injury and tubulointerstitial fibrosis in the kidneys following infection, compared with C5aR1-sufficient mice. This was associated with reduced renal leukocyte infiltration specifically for the population of Ly6Chi proinflammatory monocytes/macrophages and reduced intrarenal gene expression of key proinflammatory and profibrogenic factors in C5aR1-/- mice following infection. Antagonizing C5aR1 decreased renal bacterial load, tissue inflammation and tubulointerstitial fibrosis. Ex vivo and in vitro studies showed that under infection conditions, C5a/C5aR1 interaction upregulated the production of proinflammatory and profibrogenic factors by renal tubular epithelial cells and monocytes/macrophages, whereas the phagocytic function of monocytes/macrophages was down-regulated. Thus, C5aR1-dependent bacterial colonization of the tubular epithelium, C5a/C5aR1-mediated upregulation of local inflammatory responses to uropathogenic E. coli and impairment of phagocytic function of phagocytes contribute to persistent bacterial colonization of the kidney, chronic renal inflammation and subsequent tubulointerstitial fibrosis.