The food contaminant and nephrotoxin ochratoxin A enhances Wnt1 inducible signaling protein 1 and tumor necrosis factor-α expression in human primary proximal tubule cells.
METHODS
The underlying molecular mechanisms of nanomolar ochratoxin A (OTA) concentrations, especially those on pathophysiological relevant gene expression in target tissue and underlying signaling mechanisms are unknown.


RESULTS
qPCR arrays showed that 14 days exposure of human primary proximal tubule cells to 10 nM OTA influences the expression of genes that are related to inflammation, malignant transformation, and epithelial-to-mesenchymal transition. Wnt1 inducible signaling protein 1 (WISP1), an oncogenic, and profibrotic growth factor, turned out to be the gene with the strongest upregulation. Its expression, and that of TNF-α, an important inflammatory mediator, was further investigated in human renal cells and in primary human lung fibroblasts. OTA-induced upregulation of WISP1 and TNF-α occurs only in renal cells. Inhibition of ERK1/2 activation reverses the effect of OTA on WISP1 and TNF-α expression. Wnt or other signaling pathways were not involved. Upregulation of WISP1 and TNF-α occured independently of each other.


CONCLUSIONS
Long-term exposure of human kidney cells with OTA concentrations expectable in renal tissue due to average dietary intake leads in an ERK1/2-dependent manner to pathogenetic alterations of gene expression, notably WISP1 and TNF-α. Renal long-term risk by OTA is actually not excludable and argues for low but rational safety levels.
Julius-Bernstein-Institut für Physiologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
Isabell
I
Hennemeier
Hans-Ulrich
HU
Humpf
Michael
M
Gekle
Gerald
G
Schwerdt
D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005506:Food Contamination / Q000032:analysis*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009793:Ochratoxins / Q000032:analysis / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D009793:Ochratoxins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C025589:ochratoxin A