title: 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: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Stachurska
authors.forename: Maciej
authors.initials: M
authors.lastname: Ciesla
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozakowska
authors.forename: Siegfried
authors.initials: S
authors.lastname: Wolffram
authors.forename: Christine
authors.initials: C
authors.lastname: Boesch-Saadatmandi
authors.forename: Gerald
authors.initials: G
authors.lastname: Rimbach
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects; D035683:MicroRNAs / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009793:Ochratoxins / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D009793:Ochratoxins; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D004921:Erythropoietin; C025589:ochratoxin A; D051547:Heme Oxygenase-1; D003676:Deferoxamine; D000111:Acetylcysteine