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.

C5a Induces the Synthesis of IL-6 and TNF-α in Rat Glomerular Mesangial Cells through MAPK Signaling Pathways

“…More importantly, C5a production was earlier than IL-6 and TNF-α induction. Given that C5a is able to induce the synthesis of IL-6 and TNF-α in many other cells [26, 36–40], we hypothesized that C5a could promote the synthesis of IL-6 and TNF-α in the GMC. Notably, because there was no commercial rat C5a protein, in order to demonstrate our hypothesis, we constructed the plasmid of pET-21a/His-C5a successfully and produced recombinant rat C5a protein through prokaryotic expression.…”

Oxidative stress mediates renal endothelial cell damage in trichloroethylene-sensitized mice

“…In previous studies, renal immune injury was found in ODMLT patients and TCE-sensitized mice (Zhang et al, 2016;Zhao et al, 2012). Elevated oxidative stress was also found in TCE-sensitized guinea pig livers (Xu et al, 2010).…”

“…Trichloroethylene (TCE) is an important organic solvent widely used as a metal part cleaner, dry cleaning agent and chemical extractant (Jollow et al, 2009), which has been characterized as a human carcinogen in the Final Health Assessment in 2011 (Liu et al, 2015). TCE, usually distributed in air, soil and water, can be absorbed via the respiratory tract and the skin in workplaces (Zhang et al, 2016). Among the patients who are injured by exposure to trichloroethylene, most of the injuries are manifested as liver and kidney damage, and a small number of the patients mainly manifested severe skin lesions.…”

Viral mimic polyinosine-polycytidylic acid potentiates liver injury in trichloroethylene-sensitized mice – Viral-chemical interaction as a novel mechanism

“…Whilst Poly (I:C) may 20 have initially stimulated factor B increase to a sub-threshold level for detection, TCE could have enhanced and sustained the increase. Indeed, activation of MAPK and NF-κB pathways, which are crucial in promoting factor B synthesis (Kaczorowski et al, 2010), is identified in TCE-sensitized mice in our previous study (Zhang et al, 2015). Thus, TCE sensitization may provide a favorable environment for sustained production of B stimulated by Poly (I:C) through MAPK and NF-κB pathways.…”