Synergistic action of the nephrotoxic mycotoxins ochratoxin A and citrinin at nanomolar concentrations in human proximal tubule-derived cells
| Autor: | Luise Schumann, Ulrike Rottkord, Hans-Ulrich Humpf, Michael Gekle, Gerald Schwerdt, Marie-Christin Schulz |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Epithelial-Mesenchymal Transition MAP Kinase Signaling System Vimentin Inflammation Toxicology Cell Line Kidney Tubules Proximal 03 medical and health sciences chemistry.chemical_compound 0404 agricultural biotechnology medicine Humans Drug Interactions Epithelial–mesenchymal transition L-Lactate Dehydrogenase biology Caspase 3 Kinase Drug Synergism Epithelial Cells 04 agricultural and veterinary sciences General Medicine Mycotoxins Fibrosis Ochratoxins 040401 food science Molecular biology Citrinin Collagen Type III 030104 developmental biology chemistry biology.protein Cytokines Phosphorylation Tumor necrosis factor alpha Mitogen-Activated Protein Kinases medicine.symptom |
| Zdroj: | Toxicology Letters. 291:149-157 |
| ISSN: | 0378-4274 |
| DOI: | 10.1016/j.toxlet.2018.04.014 |
| Popis: | 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 α-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 α-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 α-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. |
| Databáze: | OpenAIRE |
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