Related Experiment Video
Updated: Feb 26, 2026
Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing
Published on: June 9, 2017
Nrf2 deficiency exacerbates ochratoxin A-induced toxicity in vitro and in vivo
Agnieszka Loboda1, Anna Stachurska1, Mateusz Sobczak1
1Department 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.
Insights
Ochratoxin A (OTA) causes kidney damage, with males being more susceptible, especially when the Nrf2 pathway is blocked. Sulforaphane (SFN) may offer protection against OTA-induced kidney injury.
Area of Science:
- Toxicology
- Molecular Biology
- Renal Physiology
Background:
- Ochratoxin A (OTA) is a mycotoxin with known nephrotoxic effects.
- The role of the Nrf2 transcription factor in OTA-induced kidney injury, particularly its sex-dependency, remains incompletely understood.
Purpose of the Study:
- To investigate the sex-dependent effects of OTA on renal injury.
- To elucidate the role of the Nrf2 pathway in OTA nephrotoxicity.
- To evaluate the potential protective effects of sulforaphane (SFN) against OTA-induced renal damage.
Main Methods:
- In vitro studies using porcine tubular epithelial cells with Nrf2 inhibition (shRNA).
- In vivo studies using Nrf2 knockout (Nrf2-/-) and wild-type male and female mice.
- Analysis of gene and microRNA expression, including pro-fibrotic, pro-inflammatory, and pro-apoptotic factors.
- Assessment of tight junction protein claudin-2 and vascular endothelial growth factor (VEGF) levels.
- Treatment with sulforaphane (SFN) in male mice.
Main Results:
- OTA toxicity was exacerbated in cells with Nrf2 inhibition and in Nrf2-/- male mice.
- Male mice exhibited significantly higher susceptibility to OTA-induced renal injury compared to females, an effect amplified in Nrf2-/- mice.
- OTA altered the expression of fibrotic, inflammatory, and apoptotic markers, reduced claudin-2 and VEGF, and upregulated miR-21, miR-34a, and miR-382.
- SFN treatment reduced OTA-induced inflammatory cytokines, apoptotic factors, and specific microRNAs in male mice.
Conclusions:
- OTA exerts a sex-dependent nephrotoxic effect, with males being more vulnerable.
- The Nrf2 pathway plays a critical protective role against OTA-induced renal pathologies.
- Targeting the Nrf2 pathway presents a potential therapeutic strategy for mitigating OTA-triggered kidney diseases.
Related Concept Videos
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...