Apoptosis and oxidative stress induced by ochratoxin A in rat kidney

Abstract

Ochratoxin A (OTA) is a widespread mycotoxin produced by several species of fungi. OTA induces a tubular-interstitial nephropathy in humans and in animals. It has been implicated as one of the aetiological agents involved in the development of endemic nephropathy. OTA-induced oxidative stress and apoptosis may play key roles in the development of chronic tubulointerstitial nephritis connected to the long-term exposure to this food contaminant. We studied the effects of low doses of OTA on kidney cells. Wistar rats were treated with 120 microg OTA/kg bodyweight daily, for 10, 30 or 60 days. Toxin concentration in kidney was proportional to the time of exposure, and amounted to 547.2, 752.5 and 930.3 ng OTA/g kidney tissue after 10, 30 and 60 days, respectively. OTA treatment caused an increased number of cells undergoing apoptosis in both proximal and distal epithelial kidney cells. The apoptotic cells were visualised using the TUNEL assay and staining with haematoxylin and eosin in situ. The number of apoptotic cells in rats treated for 10, 30 and 60 days increased by 5-, 6.4- and 12.7-fold, respectively, compared with the control cells. However, DNA electrophoresis did not show characteristic fragmentation (DNA laddering). The oxidative stress was evident via increased malondialdehyde formation. The concentration of lipid peroxides showed an increase (36%), but the activity of superoxide dismutase decreased (26%) in 60-day treated rats. In spite of the observed biochemical and morphological changes in the kidney cells, renal functional status was preserved to the end of experiment. This study demonstrates that a combination of morphologic and biochemical markers can be used to monitor early cell death in OTA-induced renal injury. We have shown that the exposure to the relatively low OTA concentrations has activated apoptotic processes and oxidative damage in kidney cells.

Ochratoxin A induces apoptosis in neuronal cells

“…In vitro and in vivo data suggest an involvement of oxidative stress in OTA-mediated cytotoxicity [1,4,16,17,23,30]. In fact, we observed in kidney tubulus cells a significant increase in reactive oxygen species production after OTA treatment already at relatively low OTA concentrations (0.5-2.5 lmol/L) [5] which were similar to those concentrations we used in the present study in neurons.…”

Ochratoxin A: Potential epigenetic mechanisms of toxicity and carcinogenicity

“…Some authors did not find any apoptotic cells in the kidney of OTA-treated animals (Mantle et al 1998) while others obtained results compatible with the presence of apoptosis (WHO 2001, O'Brien andDietrich 2005). For example, using the TUNEL assay, apoptotic cells were observed in rats given OTA (120 mg/kg bw/day) for 60 days (Petrik et al 2003). However, in this study, DNA electrophoresis did not show any characteristic fragmentation (DNAladdering).…”

“…For example, an increased formation of the lipid peroxidation product malondialdehyde (MDA) was observed in rats treated orally with 120 mg/kg bw/day of OTA over 60 days (Petrik et al 2003). In cell culture, an OTA-dependent increase in DNA damage (such as formation of 8-oxoguanine) was correlated with a production of reactive oxygen species (Schaaf et al 2002, Kamp et al 2005.…”

Ameliorative effect of emblica officinalis aqueous extract on ochratoxin-induced lipid peroxidation in the kidney and liver of mice

“…Increased malondialdehyde (MDA) production, indicating LPO increase, was reported earlier in vitro [33]. Petrik et al (2003) demonstrated that a very low concentration of ochratoxin was sufficient to induce apoptosis and oxidative damage to kidney cells in Wistar rats [34].…”