Local renal complement activation mediates immune kidney injury by inducing endothelin-1 signalling and inflammation in trichloroethylene-sensitised mice.

Trichloroethylene (TCE) is a widely used industrial solvent that causes trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including kidney injury. Clinical studies have shown that the complement system is important for TCE-induced kidney injury. Our previous study found excessive deposition of complement C3, mainly on the glomerulus, indicating that local renal complement is activated after TCE sensitisation. However, whether local renal complement activation mediates TCE-induced immune kidney injury and the underlying mechanisms remain unknown. Therefore, we established a TCE percutaneous sensitisation BALB/c mouse model to explore the mechanisms by pretreating with or without the complement activation antagonist, cathepsin L inhibitor (CatLi). As expected, more C3 and C3a were detected mainly on glomerulus of TCE positive sensitisation (TCE+) mice. Renal dysfunction and pathological damage were also clearly observed in TCE+ mice. Moreover, the mRNA and protein expression of ET-1 increased significantly with local renal complement activation after TCE sensitisation, leading to cytokines release and inflammation. In addition, activation of p38MAPK and NF-κBp65 pathways were detected in kidneys of TCE+ mice, and CatLi pretreatment decreased these changes through complement activation antagonisation. Our research uncovered a novel role of local renal complement activation during immune kidney injury after TCE sensitisation through induction of ET-1 signalling and inflammation.