Terminal complement complex C5b-9 reduced megalin and cubilin-mediated tubule proteins uptake in a mouse model of trichloroethylene hypersensitivity syndrome. (15th December 2019)

• Record Type: Journal Article
• Authors: Wang, Feng; Huang, Li-ping; Dai, Yu-ying; Huang, Meng; Jiang, Wei; Ye, Liang-ping; Zhu, Qi-xing
• Is Part Of: Toxicology letters. Volume 317(2019)
• Page Start: 110
• Page End: 119
• Publication Date: 2019-12-15
• Subjects: Trichloroethylene -- Renal tubules -- C5b-9 -- Megalin -- Cubilin; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.10.002
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: TCE sensitization induced structural and functional disorders of renal tubules and deposition of C5b-9. C5b-9 located on proximal tubular epithelial cells and played a sub-lytic effect. Megalin and cubilin receptors were down-regulated in damaged renal tubules. CD59 pretreatment blocked the deposition of C5b-9, and ameliorated the urinary protein uptake. CD59 pretreatment also recovered the expression of megalin and cubilin receptors. Abstract: Trichloroethylene (TCE), a commonly used industrial solvent and degreasing agent, is known to cause trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including skin, liver and kidney. Clinical evidence have shown that the kidney injury occurs in THS and our previous studies suggested that the terminal complement complex C5b-9 deposited in impaired renal tubules induced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the complement system with renal deposition of C5b-9 contributes to TCE-induced kidney injury in THS. We established a BALB/c mouse model of TCE sensitization with or without pretreatment of exogenous CD59, a C5b-9 inhibitory protein. H&E staining, PAS staining, and biochemical detection of urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of CD59 were evaluated by immunohistochemistry. Sub-lytic effects of C5b-9 in tubular epithelial cells were assessed by lactate dehydrogenase (LDH) cytotoxicity assay. Expression of endocytosis receptors megalin and cubilin on proximal tubules were assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal tubules in mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased proximal tubule uptake of filtered proteins and renal expression of megalin and cubilin, phenotypes that were attenuated by pretreatment with exogenous CD59. Overall, our findings reveal a novel mechanism underlying sub-lytic C5b-9 acting on megalin and cubilin, contributes to the renal tubules damage by TCE exposure.