Mitochondrial dysfunction is an early event in ochratoxin a but not oosporein toxicity to rat renal proximal tubules

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Abstract

Ochratoxin A (OA) and oosporein (OSN) are two mycotoxins that may cause nephrotoxicity through either mitochondrial dysfunction or lipid peroxidation. Using isolated rat renal proximal tubules in suspension, the cellular events preceding OA- or OSN-induced cytotoxicity were investigated. OA and OSN decreased tubule viability in a concentration (0–1 mm)- and time (0–4 hr)-dependent manner, with initial decreases occurring 1 hr after exposure. Tubule basal and nystatin-stimulated oxygen consumption decreased before cell death after OA (0.5 and 1 mm) and 0.25 mm t-butyl hydroperoxide (TBHP) exposure, but did not decrease after OSN exposure (0.25–1 mm). The oxidant TBHP was used as a positive control in these studies. Direct probing of mitochondrial function within proximal tubules confirmed the toxicity of OA to mitochondria. Respiration was reduced in the absence and presence of a phosphate acceptor using site I (glutamate/malate) and site II (succinate) respiratory substrates 15 and 30 min after exposure to 1 mm OA. Lipid peroxidation preceded cell death after exposure to 1 mm OA and 0.25 mm TBHP, but did not occur after exposure to 1 mm OSN. Deferoxamine (1 mm) pretreatment before the addition of 1 mm OA or OSN prevented OA-induced lipid peroxidation, but did not prevent OA- or OSN-induced cytotoxicity. In contrast, deferoxamine pretreatment prevented lipid peroxidation, mitochondrial dysfunction, and the loss of tubule viability after exposure to 0.25 mm TBHP. This study shows that mitochondrial dysfunction is an early event during the development of OA toxicity, but not in OSN-induced toxicity. Furthermore, iron-mediated lipid peroxidation does not contribute to OA- or OSN-induced proximal tubule cell death.

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    OTA cytotoxicity reported here is similar to that for OTA in other cell lines, including Caco-2 cells, mouse RAW264.7 macrophages and Madin-Darby Bovine Kidney (MDBK) cells (Clarke et al., 2014), Vero cells (Bouslimi et al., 2008; Golli-Bennour et al., 2010) and porcine PK15 cells (Klarić et al., 2008, 2012). The cytotoxic effect of OTA, particularly at high concentrations can be attributed to the fact that OTA has the ability to inhibit protein synthesis (Creppy et al., 1983), impair mitochondrial phosphorylation (Wei et al., 1985; Aleo et al., 1991); disrupt the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-dependent pathway resulting to lipid peroxidation, proteolytic stress and oxidative DNA damage (Cavin et al., 2007, 2009; Limonciel and Jennings, 2014), induce cell apoptosis (Schwerdt et al., 1999; Schilter et al., 2005; Rached et al., 2006; Malir et al., 2016), and dysregulate mitosis by interfering with the activity of histone acetyltransferases (Adler et al., 2009; Czakai et al., 2011; Mally, 2012). In this study, AFB1 was not very cytotoxic to MA-10 cells, with only a slight increase in toxicity seen above 8 μM.

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