Molecular Medicine

, Volume 11, Issue 1–12, pp 30–38 | Cite as

Ochratoxin A-Induced Renal Cortex Fibrosis and Epithelial-to-Mesenchymal Transition: Molecular Mechanisms of Ochratoxin A-Injury and Potential Effects of Red Wine

  • Nicoletta Gagliano
  • Carlo Torri
  • Elena Donetti
  • Fabio Grizzi
  • Francesco Costa
  • Alberto A E Bertelli
  • Massimiliano Migliori
  • Cristina Filippi
  • Marzia Bedoni
  • Vincenzo Panichi
  • Luca Giovannini
  • Magda Gioia


We characterized the effect of chronic ochratoxin A (OTA) on rat kidney cortex, analyzing collagen content and collagen turnover and the major markers of epithelial-to-mesenchymal transition (EMT), such as α-smooth muscle actin (αSMA), cadherins, and MMP-9. Because OTA nephrotoxicity is mediated by free radicals, we also investigated whether antioxidants in red wine provided protection for the kidney and attenuated OTA-induced EMT. Collagen content, determined by computerized analysis of Sirius red-stained kidney sections, increased in OTA, OTA-wine, and OTA-EtOH treated rats. In kidney cortex homogenates, COL-I and COL-III mRNA levels tended to rise in OTA treated rats, but were similar to CT after OTA-wine and OTA-EtOH administration. TIMP-1 gene expression was up-regulated in OTA, OTA-wine, and OTA-EtOH treated rats. LH2b mRNA/COL-I mRNA was significantly up-regulated in OTA-wine and OTA-EtOH treated rats, compared with CT and OTA alone. TGF-βl signaling tended to dominate after OTA, OTA-wine, and OTA-EtOH. MMP-1 protein levels were not affected. OTA induced proMMP-9 and αSMA overexpression, decreases of E-cadherin and N-cadherin, and DSC-2 up-regulation. OTA-wine caused a further, unexpected decrease of E- and N-cadherins and further up-regulation of OTA-induced DSC-2, while strongly reducing the OTA-induced increases of αSMA and proMMP-9. Posttranslational collagen modifications, such as decreased collagen degradation through MMP inhibition and increased collagen cross-links, seem to be key mechanisms leading to OTA-induced kidney cortex fibrosis. This mechanism was not affected by red wine in these conditions. Red wine seems to have some protective role against OTA-induced EMT, although without completely blocking the process and determining a condition in which abundant cells display an intermediate translational phenotype, but there are no αSMA or epithelial markers.



We thank Silvia Celon and Osvaldo De Negri for their technical support and J.D. Baggott for editing the text. This work was supported by a grant of the Italian Government (Ministero delle Politiche Agricole e Forestali, MPAF) Targeted Project.


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Copyright information

© Feinstein Institute for Medical Research 2005

Authors and Affiliations

  • Nicoletta Gagliano
    • 1
  • Carlo Torri
    • 1
  • Elena Donetti
    • 1
  • Fabio Grizzi
    • 2
  • Francesco Costa
    • 1
  • Alberto A E Bertelli
    • 1
  • Massimiliano Migliori
    • 3
  • Cristina Filippi
    • 3
  • Marzia Bedoni
    • 1
  • Vincenzo Panichi
    • 3
  • Luca Giovannini
    • 3
  • Magda Gioia
    • 1
  1. 1.Department of Human Morphology - LITA SegrateUniversity of MilanSegrate, MilanoItaly
  2. 2.Scientific DirectionIstituto Clinico Humanitas, Rozzano and “M. Rodriguez” Foundation, Institute for Quantitative Measures in MedicineMilanItaly
  3. 3.Department of Neuroscience (Pharmacology section) and Internal MedicineUniversity of PisaPisaItaly

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