title: Complement C5a-C5aR interaction enhances MAPK signaling pathway activities to mediate renal injury in trichloroethylene sensitized BALB/c mice.
abstract: We have previously shown complement activation as a possible mechanism for trichloroethylene (TCE) sensitization, leading to multi-organ damage including the kidneys. In particular, excessive deposition of C5 and C5b-9-the membrane attack complex, which can generate significant tissue damage, was observed in the kidney tissue after TCE sensitization. The present study tested the hypothesis that anaphylatoxin C5a binding to its receptor C5aR mediates renal injury in TCE-sensitized BALB/c mice. BALB/c mice were sensitized through skin challenge with TCE, with or without pretreatment by the C5aR antagonist W54011. Kidney histopathology and the renal functional test were performed to assess renal injury, and immunohistochemistry and fluorescent labeling were carried out to assess C5a and C5aR expressions. TCE sensitization up-regulated C5a and C5aR expressions in kidney tissue, generated inflammatory infiltration, renal tubule damage, glomerular hypercellularity and impaired renal function. Antagonist pretreatment blocked C5a binding to C5aR and attenuated TCE-induced tissue damage and renal dysfunction. TCE sensitization also caused the deposition of major pro-inflammatory cytokines IL-2, TNF-α and IFN-γ in the kidney tissue (P < 0.05); this was accompanied by increased expression of P-p38, P-ERK and P-JNK proteins (P < 0.05). Pretreatment with the C5aR antagonist attenuated the increase of expression of P-p38, P-ERK and P-JNK proteins (P < 0.05) and also consistently reduced the TCE sensitization-induced increase of IL-2, TNF-α and IFN-γ (P < 0.05). These data identify C5a binding to C5aR, MAP kinase activation, and inflammatory cytokine release as a novel mechanism for complement-mediated renal injury by sensitization with TCE or other environmental chemicals.
authors.affiliation: Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Jia-xiang
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: Anhui NO.2 Province People's Hospital, Hefei, Anhui, China.
authors.forename: Wan-sheng
authors.initials: WS
authors.lastname: Zha
authors.affiliation: Institute of Dermatology, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China.
authors.forename: Liang-ping
authors.initials: LP
authors.lastname: Ye
authors.affiliation: Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Occupational Health and Environment Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China.|Institute of Dermatology, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors.forename: Chang-hao
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Institute of Dermatology, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China.
authors.forename: Qi-xing
authors.initials: QX
authors.lastname: Zhu
mesh_terms: D000818:Animals; D015936:Complement C5a / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D015398:Signal Transduction / Q000187:drug effects; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: D014241:Trichloroethylene; D015936:Complement C5a; D020928:Mitogen-Activated Protein Kinases
keywords: C5a; C5aR; MAPK; renal injury; trichloroethylene