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Toxicology. 2017 Aug 15;389:42-52. doi: 10.1016/j.tox.2017.07.004. Epub 2017 Jul 12.

Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo.

Author information

1
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address: agnieszka.loboda@uj.edu.pl.
2
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.

Abstract

Several mechanisms are postulated to be responsible for nephrotoxic and nephrocarcinogenic activities of mycotoxin and food contaminant, ochratoxin A (OTA). Although Nrf2 transcription factor was suggested to be involved in OTA-mediated renal injury, comprehensive study evaluating the effect of OTA toxicity in Nrf2 knock-out mice with special regard to sex-dependency has not been performed yet. Our results clearly show exacerbated OTA toxicity in porcine tubular epithelial cells after shRNA-mediated Nrf2 inhibition as well as in proximal tubular cells isolated from Nrf2-/- male mice in comparison to cells derived from their wild-type counterparts. In vivo study revealed that male mice are significantly more susceptible to OTA-mediated injury than females and this effect was further enhanced in mice lacking Nrf2. OTA increased the expression of pro-fibrotic, pro-inflammatory and pro-apoptotic factors, while concomitantly decreased the level of claudin-2 and vascular endothelial growth factor (VEGF). Importantly, miR-21, miR-34a and miR-382 were potently up-regulated after OTA delivery. Noteworthy, treatment with sulforaphane (SFN), diminished expression of OTA-induced inflammatory cytokines (IL-1β, IL-6), pro-apoptotic factors (c-myc, PUMA) and microRNAs (miR-382, miR-34a) in male mice. In summary, our data implies sex-dependent effect of OTA, with males being more sensitive. The lack of Nrf2 enhances susceptibility to mycotoxin-induced pathologies, suggesting that modulation of the Nrf2 pathway may provide a therapeutic approach to treat OTA-triggered renal diseases.

KEYWORDS:

Kidney diseases; Mycotoxin; Nephrotoxicity; Nrf2; Nuclear factor E2-related factor 2; microRNA

PMID:
28710020
DOI:
10.1016/j.tox.2017.07.004
[Indexed for MEDLINE]

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