Mitochondrial dysfunction is an early event in ochratoxin A but not oosporein toxicity to rat renal proximal tubules.
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.
Aleo
M D
MD
Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30602.
Wyatt
R D
RD
Schnellmann
R G
RG
D000818:Animals; D016227:Benzoquinones / Q000633:toxicity*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009793:Ochratoxins / Q000633:toxicity*; D010101:Oxygen Consumption; D010545:Peroxides / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D020122:tert-Butylhydroperoxide
D016227:Benzoquinones; D009793:Ochratoxins; D010545:Peroxides; C025589:ochratoxin A; C008706:oosporein; D020122:tert-Butylhydroperoxide; D007770:L-Lactate Dehydrogenase