Cross-talk between microRNAs, nuclear factor E2-related factor 2, and heme oxygenase-1 in ochratoxin A-induced toxic effects in renal proximal tubular epithelial cells.

Abstract

SCOPE:

Ochratoxin A (OTA) is a mycotoxin exhibiting nephrotoxic and potential carcinogenic activity. We investigated the cross-talk between microRNAs, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in ochratoxin A-mediated effects.

METHODS AND RESULTS:

In porcine renal proximal tubular cells, OTA increased expression of profibrotic transforming growth factors β (TGFβ) while concomitantly decreasing expression of Nrf2, HO-1, and erythropoietin. Adenoviral overexpression of Nrf2 counteracted OTA-mediated reduction in HO-1 and erythropoietin expression and cell proliferation as well as increase in reactive oxygen species (ROS) generation and TGFβ expression. Additionally, inhibition of HO activity enhanced whereas adenoviral overexpression of HO-1 reduced expression of TGFβ. Moreover, antioxidants, N-acetyl-cysteine and desferioxamine, prevented OTA-mediated enhancement of ROS generation, and TGFβ expression. Finally, OTA modulated microRNA processing by upregulating LINeage protein 28 and DiGeorge syndrome critical region-8, increasing the total pool of cellular microRNAs and elevating the expression of miR-132 and miR-200c. Inhibition of miR-132 by specific antagomir restored the OTA-driven reduction in Nrf2 expression. Moreover, anti-miR-132 and anti-miR-200c counteracted OTA-mediated decrease in HO-1 levels as well as increase in ROS production and TGFβ expression.

CONCLUSION:

We showed that attenuation of Nrf2 and HO-1 expression through induction of miR-132 and miR-200c by OTA elevates ROS levels and profibrotic TGFβ expression.

• Authors: Anna Stachurska, Maciej Ciesla, Magdalena Kozakowska, Siegfried Wolffram, Christine Boesch-Saadatmandi, Gerald Rimbach, Alicja Jozkowicz, Jozef Dulak, Agnieszka Loboda
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 57 Issue 3 Pg. 504-15 (Mar 2013) ISSN: 1613-4133 [Electronic] Germany
• PMID: 23281030 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antioxidants
• MicroRNAs
• NF-E2-Related Factor 2
• Ochratoxins
• Reactive Oxygen Species
• Transforming Growth Factor beta
• Erythropoietin
• ochratoxin A
• Heme Oxygenase-1
• Deferoxamine
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Cells, Cultured
• Deferoxamine (pharmacology)
• Epithelial Cells (drug effects, metabolism)
• Erythropoietin (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Heme Oxygenase-1 (genetics, metabolism)
• Kidney Tubules, Proximal (cytology, drug effects)
• MicroRNAs (metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Ochratoxins (toxicity)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Swine
• Transforming Growth Factor beta (genetics, metabolism)