Question: 

The kidney is a common target for toxic substances, which can cause serious renal damage. Ochratoxin A (OTA) is a mycotoxin which has both nephrotoxic and carcinogenic potential. The underlying changes of gene expression responsible for nephrotoxicity and cancerogenity are still unproven. Previous investigations showed that OTA increases gene expression of Wnt1 inducible signaling protein 1 (WISP1), a profibrotic and oncogenic growth factor. We investigated signaling pathways that may be involved in OTA-induced WISP1 expression.

Methodology: 

Renal proximal tubule cells in primary culture (RPTEC) and human embryonic kidney cells (HEK293) were treated with 10 nM OTA, with and without several kinase inhibitors for up to 14 days. WISP1 mRNA was detected by RT-PCR and qRT-PCR. Western Blot for ERK1/2, CREB and b-catenin was performed on cell lysates.

Results: 

10 nM OTA increases WISP1 gene expression in RPTEC and HEK293. CREB was activated in RPTEC, ERK1/2 in both RPTEC and HEK293 cells. b-catenin protein expression did not change. p38, JNK, MSK1, PKA and PKC-inhibitors had no effect on OTA-induced WISP1 expression, whereas inhibition of MEK1/2 significantly reduced WISP1 gene expression as well as ERK1/2 and CREB phosphorylation.

Conclusion: 

Exposure of human kidney cells with OTA concentrations detectable in human renal tissue up-regulates the expression of WISP1. Although it was originally supposed that WISP1 is a target of the canonical WNT/b-catenin pathway we found that OTA leads to an ERK1/2-CREB-mediated WISP1 expression. WISP1 signaling could be involved in fibrotic changes in renal tissue and tumorigenesis caused by OTA.