title: The complement factor 5a receptor 1 has a pathogenic role in chronic inflammation and renal fibrosis in a murine model of chronic pyelonephritis.
abstract: 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.
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Naheed
authors.initials: N
authors.lastname: Choudhry
authors.affiliation: Core Research Laboratory, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China. Electronic address: ke.li@xjtu.edu.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Core Research Laboratory, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Core Research Laboratory, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Kun-Yi
authors.initials: KY
authors.lastname: Wu
authors.affiliation: Core Research Laboratory, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Farrar
authors.affiliation: Core Research Laboratory, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Core Research Laboratory, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Cheng-Fei
authors.initials: CF
authors.lastname: Liu
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Qi
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Weiju
authors.initials: W
authors.lastname: Wu
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Sacks
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London, UK. Electronic address: wuding.zhou@kcl.ac.uk.
authors.forename: Wuding
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000950:Antigens, Ly; D058491:Bacterial Load; D002908:Chronic Disease; D015936:Complement C5a / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D004927:Escherichia coli Infections / Q000473:pathology*; D005355:Fibrosis; D007249:Inflammation / Q000473:pathology*; D007668:Kidney / Q000166:cytology / Q000473:pathology*; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D011704:Pyelonephritis / Q000473:pathology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056689:Uropathogenic Escherichia coli / Q000302:isolation & purification*
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D000950:Antigens, Ly; C000591759:C5ar1 protein, mouse; C494192:Ly-6C antigen, mouse; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a
keywords: C5aR1; chronic inflammation; pyelonephritis; renal fibrosis