Toxicity of depleted uranium on isolated rat kidney mitochondria |
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Authors: | Fatemeh Shaki Mir-Jamal Hosseini Mahmoud Ghazi-Khansari Jalal Pourahmad |
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Affiliation: | 1. Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran;2. Faculty of Pharmacy, Mazandaran University of Medical Sciences, sari, Mazandaran Pharmaceutical Sciences Research Center, Iran;3. Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran;4. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran |
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Abstract: | BackgroundKidney is known as the most sensitive target organ for depleted uranium (DU) toxicity in comparison to other organs. Although the oxidative stress and mitochondrial damage induced by DU has been well investigated, the precise mechanism of DU-induced nephrotoxicity has not been thoroughly recognized yet.MethodsKidney mitochondria were obtained using differential centrifugation from Wistar rats and mitochondrial toxicity endpoints were then determined in both in vivo and in vitro uranyl acetate (UA) exposure cases.ResultsSingle injection of UA (0, 0.5, 1 and 2 mg/kg, i.p.) caused a significant increase in blood urea nitrogen and creatinine levels. Isolated mitochondria from the UA-treated rat kidney showed a marked elevation in oxidative stress accompanied by mitochondrial membrane potential (MMP) collapse as compared to control group. Incubation of isolated kidney mitochondria with UA (50, 100 and 200 μM) manifested that UA can disrupt the electron transfer chain at complex II and III that leads to induction of reactive oxygen species (ROS) formation, lipid peroxidation, and glutathione oxidation. Disturbances in oxidative phosphorylation were also demonstrated through decreased ATP concentration and ATP/ADP ratio in UA-treated mitochondria. In addition, UA induced a significant damage in mitochondrial outer membrane. Moreover, MMP collapse, mitochondrial swelling and cytochrome c release were observed following the UA treatment in isolated mitochondria.General significanceBoth our in vivo and in vitro results showed that UA-induced nephrotoxicity is linked to the impairment of electron transfer chain especially at complex II and III which leads to subsequent oxidative stress. |
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Keywords: | U, Uranium DU, Depleted uranium UA, uranyl acetate ROS, Reactive oxygen species GSH, reduced glutathione DCF-DA, 2&prime ,7&prime -dichlorofluorescein diacetate TBARs, thiobarbituric acid reactive substances Cs A, Cyclosporin A MDA, Malondialdehyde Rh123, Rhodamine 123 BSA, bovine serum albumin MPT, mitochondrial permeability transition MMP, mitochondrial membrane potential BHT, butylatedhydroxytoluene BUN, blood urea nitrogen |
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