Terminal complement complex C5b-9 reduced megalin and cubilin-mediated tubule proteins uptake in a mouse model of trichloroethylene hypersensitivity syndrome
2019
Abstract
Trichloroethylene(TCE), a commonly used industrial solvent and
degreasingagent, is known to cause
trichloroethylenehypersensitivity 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 complexC5b-9 deposited in impaired renal
tubulesinduced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the
complement systemwith 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 detectionof urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of
CD59were 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
cubilinon
proximal tubuleswere assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal
tubulesin mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased
proximal tubuleuptake 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
tubulesdamage by TCE exposure.
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