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

Scope 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. Methods and results q PCR 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 ( WISP 1), 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 WISP 1 and TNF ‐α occurs only in renal cells. Inhibition of ERK 1/2 activation reverses the effect of OTA on WISP 1 and TNF ‐α expression. W nt or other signaling pathways were not involved. Upregulation of WISP 1 and TNF ‐α occured independently of each other. Conclusion Long‐term exposure of human kidney cells with OTA concentrations expectable in renal tissue due to average dietary intake leads in an ERK 1/2‐dependent manner to pathogenetic alterations of gene expression, notably WISP 1 and TNF ‐α. Renal long‐term risk by OTA is actually not excludable and argues for low but rational safety levels.