Synergistic action of the nephrotoxic mycotoxins ochratoxin A and citrinin at nanomolar concentrations in human proximal tubule-derived cells

被引:32
|
作者
Schulz, Marie-Christin [1 ]
Schumann, Luise [1 ]
Rottkord, Ulrike [2 ]
Humpf, Hans-Ulrich [2 ]
Gekle, Michael [1 ]
Schwerdt, Gerald [1 ]
机构
[1] Martin Luther Univ Halle Wittenberg, Julius Bernstein Inst Physiol, Magdeburger Str 6, D-06112 Halle, Germany
[2] Westfalische Wilhelms Univ Munster, Inst Lebensmittelchem, Munster, Germany
关键词
Ochratoxin A; Citrinin; Proximal tubule; Epithelial-to-mesenchymal transition; Tubulo-interstitial nephropathy; MESENCHYMAL TRANSITION; ENDEMIC NEPHROPATHY; ACTIVATION; EXPRESSION; TOXICITY; PATHWAYS; EXPOSURE; FIBROSIS; ADULTS; LEVEL;
D O I
10.1016/j.toxlet.2018.04.014
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Increased ochratoxin A (OTA) or citrinin (CIT) concentrations in food correlate with increased prevalence of tubule-interstitial nephropathy. We tested the hypothesis that co-exposure of human proximal tubule-derived epithelial cells (HK-2) to OTA and CIT promotes synergistic events indicative for inflammation, epithelial-to-mesenchymal-transition (EMT) or fibrosis. We measured markers of inflammation, EMT and fibrosis and investigated the role of MAP-kinases. Only concurrent but not individual exposure to OTA and CIT at nanomolar concentrations led to (i) an increase of TNF protein and mRNA, (ii) a decrease of COX-2 protein and mRNA, (iii) a decrease of E-cadherin protein and (iv) an increase of vimentin and alpha-SMA protein. Cell shape shifted from a cobblestone-to a spindle-like phenotype indicating EMT. Extra-and intracellular collagen III protein content was increased. Concomitant mRNA expression changes were observed for TNF, COX-2, E-cadherin and alpha-SMA indicating transcriptional regulation. This was not the case for vimentin and collagen III mRNA indicating posttranscriptional regulation. Inhibition of ERK 1/2 and JNK 1/2 reduced the effect on TNF but not on alpha-SMA mRNA indicating an involvement of these kinases. Phosphorylation of ERK1/2 was increased by CIT, OTA alone and the mycotoxin combination. In contrast, the phosphorylation of JNK1/2 was unchanged. In conclusion, nanomolar OTA and CIT act synergistically favouring nephropathic processes.
引用
收藏
页码:149 / 157
页数:9
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