期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 75, 期 6, 页码 1117-1132出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-017-2687-6
关键词
Microcystin-leucine-arginine; MMP-8; Transcriptional and post-transcriptional levels; Occludin degradation
资金
- National Natural Science Foundation of China [31370524, 21377052, 31670519]
- Fundamental Research Funds for the Central Universities [021414380332]
Microcystin-leucine-arginine (MC-LR) can cause male reproductive disorders. However, the underlying mechanisms are not yet fully understood. In this study, we aimed to investigate the effects of MC-LR on the integrity of blood-testis barrier (BTB) and the related molecular mechanisms. Both transepithelial electrical resistance measurement in vitro and electron microscope observation ex vivo revealed that MC-LR caused disruption of the tight junction between Sertoli cells, which was paralleled by the degradation of occludin. We observed increased expression of matrix metalloproteinase-8 (MMP-8) upon exposure to MC-LR, and confirmed that abrogation of MMP-8 activity by specific inhibitors as well as transfection with MMP-8 shRNA could abolish the degradation of occludin. Our data demonstrated that MC-LR up-regulated nuclear levels of c-Fos and c-Jun through activating ERK and JNK, and increased NF-kappa B levels by activating the phosphatidylinositol 3-kinase (PI3K)/AKT cascades. Enhanced binding of c-Fos and NF-kappa B to the promoter of MMP-8 promoted the transcription of MMP-8 gene. Furthermore, miR-184-3p was significantly downregulated in SC following exposure to MC-LR through targeting MMP-8 expression. Together, these results confirmed that MC-LR-induced MMP-8 expression was regulated at both transcriptional and post-transcriptional levels, which was involved in MC-LR-induced degradation of occludin and BTB destruction. This work may provide new perspectives in developing new diagnosis and treatment strategies for MC-induced male infertility.
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