Ochratoxin A cytotoxicity on Madin–Darby canine kidney cells in the presence of alpha‐tocopherol: Effects on cell viability and tight junctions

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Ochratoxin A (OTA) is a potent nephrotoxic metabolite produced by several species of fungi of the genera Aspergillus and Penicillium. Ochratoxin A occurs in several agricultural products and causes diseases both in humans and animals (O'Brien & Dietrich, 2005; Pfohl‐Leszkowicz & Manderville, 2007). International organizations and agencies as well as expert groups have reviewed the literature on the data in order to provide updates on OTA toxicity and the risks related to feed/food contamination for animal and human health (Bui‐Klimke & Wu, 2015; Denli & Perez, 2010; EFSA, 2006; IARC, 1993; JECFA, 2007). Ochratoxin A has carcinogenic, nephrotoxic, teratogenic, immunotoxic and possibly neurotoxic properties. The kidney has been considered one of the main target organs of OTA toxicity. The mechanism of action by which OTA exerts its toxicity is mainly related to the concentration and duration of the exposure (Gekle, Sauvant, & Schwerdt, 2005; Petrik et al., 2005). Several studies conducted by various researchers have suggested that OTA mediates its toxicity via direct and unspecific inhibition of macromolecule synthesis, DNA adduct formation, lipid peroxidation, oxidative damage and uncoupling mitochondria, exhibiting the so‐called primary non‐specific action, as described by Gekle et al. (2005), when present at high concentrations (>μM). At nM concentrations, this mycotoxin induces MAPK activation and apoptosis (Gekle et al., 2005). In particular, OTA is able to cause cell perturbations that can lead to cell death. One of the mechanisms responsible for this alteration is OTA‐induced oxidative stress, which causes membrane and/or DNA damage, determining the beginning of the necrotic or apoptotic processes (Giromini et al., 2016; Marin‐Kuan, Ehrlich, Delatour, Cavin, & Schilter, 2011; O'Brien & Dietrich, 2005).
Increasing evidence has suggested that OTA is responsible of the perturbation of cell–cell interactions as well as cell–cell signalling (Gekle et al., 2000; González‐Mariscal, Nava, & Hernández, 2005; Mally, Decker, Bekteshi, & Dekant, 2006; Mc Laughlin, Padfield, Burt, & O'Neil, 2004; Schramek et al., 1997). Tight junctions represent the most apical components of the intercellular junctional complex, which also includes adherens junctions, desmosomes and gap junctions. Tight junctions are composed of multiple transmembrane, scaffolding and signalling proteins, between which occludin and Zo1 interact to connect with the actin cytoskeleton (Harhaj & Antonetti, 2004). In the kidney, tight junctions vary along the nephron. The level of complexity of the tight junction increases moving forward in the distal tubule. Madin–Darby canine kidney (MDCK) cells represent an estimable model of the distal tubule/collecting duct (Feldman, Mullin, & Ryan, 2005) and have been used for OTA toxicity studies (Gekle et al., 2000; Schramek et al., 1997).
Several strategies, including some nutrient supplementation, have been proposed to reduce OTA toxicity (Denli & Perez, 2010; Sorrenti et al., 2013). Among them, antioxidant molecules, such as vitamin E, vitamin A, lycopene and phenolic compounds, have been shown to demonstrate different beneficial effects in blocking OTA toxicity in vivo and in vitro and have gained a key role in promoting health (Sorrenti et al., 2013). The role of α‐tocopherol in counteracting OTA cytotoxicity has been demonstrated in several in vitro models (Baldi et al., 2004; Fusi et al., 2010). This compound could be able to reduce the damage induced by OTA at different cellular levels. In particular, the preferential localization of α‐tocopherol in the cell membranes enhances its functional role as a lipid antioxidant and membrane stabilizer (Wang & Quinn, 1999).
The aim of this study was to evaluate the effects of OTA on cell viability, apoptotic rate and occludin and Zo1 localization, and the role of α‐tocopherol in counteracting its effects in MDCK cells.
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