Ochratoxin A-induced renal cortex fibrosis and epithelial-to-mesenchymal transition: molecular mechanisms of ochratoxin A-injury and potential effects of red wine.
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 alpha-smooth muscle actin (alphaSMA), 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-beta1 signaling tended to dominate after OTA, OTA-wine, and OTA-EtOH. MMP-1 protein levels were not affected. OTA induced proMMP-9 and alphaSMA 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 alphaSMA 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 alphaSMA or epithelial markers.
Gagliano
Nicoletta
N
Department of Human Morphology, University of Milan, Italy. nicoletta.gagliano@unimi.it
Torri
Carlo
C
Donetti
Elena
E
Grizzi
Fabio
F
Costa
Francesco
F
Bertelli
Alberto A E
AA
Migliori
Massimiliano
M
Filippi
Cristina
C
Bedoni
Marzia
M
Panichi
Vincenzo
V
Giovannini
Luca
L
Gioia
Magda
M
D000818:Animals; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004848:Epithelium / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity; D005355:Fibrosis / Q000139:chemically induced; D007672:Kidney Cortex / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000187:drug effects*; D009793:Ochratoxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D014920:Wine
D004338:Drug Combinations; D009793:Ochratoxins; C025589:ochratoxin A; D000431:Ethanol