Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo. (15th August 2017)

• Record Type: Journal Article
• Authors: Loboda, Agnieszka; Stachurska, Anna; Sobczak, Mateusz; Podkalicka, Paulina; Mucha, Olga; Jozkowicz, Alicja; Dulak, Jozef
• Is Part Of: Toxicology. Volume 389(2017)
• Page Start: 42
• Page End: 52
• Publication Date: 2017-08-15
• Subjects: AP alkaline phosphatase -- BEN Balkan endemic nephropathy -- EMT epithelial to mesenchymal cell transition -- γ-GTP γ-glutamyltranspeptidase -- HO-1 heme oxygenase-1 -- IARC The International Agency for Research on Cancer -- LDH lactate dehydrogenase -- LLC-PK1 porcine kidney epithelial cell line -- Nrf2 nuclear factor E2-related factor 2 -- OTA ochratoxin A -- ROS reactive oxygen species -- RPTEC primary renal proximal tubular cells -- RT room temperature -- SFN sulforaphane -- TGFβ transforming growth factor β -- VEGF vascular endothelial growth factor; Nephrotoxicity -- microRNA -- Nuclear factor E2-related factor 2 -- Nrf2 -- Mycotoxin -- Kidney diseases; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.07.004
• Languages: English
• ISSNs: 0300-483X

Abstract

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, mi R -34a and mi R -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 (mi R -382, mi R -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.