The protection of selenium on adriamycin-induced mitochondrial damage in rat.
ABSTRACT Although adriamycin (ADR) exhibits high anti-tumor efficacy in vitro, its clinical use in cancer chemotherapy is limited due to its high renal toxicity. This study investigated the mechanism of ADR nephropathy and the protective effect of selenium on ADR-induced kidney damage by analyzing of the relationship between selenium and mitochondria. Rats were divided into four groups. The first group was injected with saline i.p. for 21 days, the second group received the 4 mg/kg i.p. ADR every alternate day for 8 days, the third group received the 50 μg/kg i.p. Se for 21 days, and the fourth group received the Se. ADR co-administration i.p. blood pressures were assessed, the mitochondrial membrane potential (MMP) was assessed, and the adenosine triphosphate (ATP) levels were determined. The total antioxidant (TAS) and oxidant status (TOS) in cytosol, the mitochondria of kidney cells, and plasma were measured. Mitochondrial TAS decreased and TOS increased in the ADR group compared to the Se group. ADR-treated rats showed significantly lower MMP than did the control and Se groups. MMP was significantly restored in the Se + ADR group through selenium treatment compared to the ADR group (p < 0.01). In the ADR group, a reduction in ATP content was seen compared to the control and Se groups (p < 0.01). ATP level was significantly restored through treatment with selenium in the Se + ADR group compared to the ADR group (p < 0.01). We concluded that selenium is effective in vivo against ADR-induced kidney damage via the restoration of TAS and TOS, which prevented mitochondrial damage.
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ABSTRACT: Selenium (Se) is an essential trace element in animals and human, however, excess Se intake can result in adverse health effects. Se supplementation increased glutathione peroxidase (GSH-Px) and thioredoxin reductase (TR) expressions in Se-deficient rats. However, little information is available on the relationship between Se overexposure on GSH-Px and TR mRNA levels and activities. In this study, the effects of Se overexposure on GSH-Px and TR mRNA levels and activities were investigated by reverse transcription-polymerase chain reaction (RT-PCR) and activity assay. Experimental groups of male Wistar rats were injected intraperitoneally (i.p.) with sodium selenite at doses of 20, 40, and 80 microg Se/kg/d for 15 d, respectively. Se levels were elevated dose-dependently in rat liver, kidney, and testis tissues. GSH-Px mRNA levels and activities in the liver and testis for rats injected with 20 microg Se/kg/d were increased significantly as compared with those in the control group. However, intraperitoneal injection of 40 and 80 microg Se/kg/d dramatically decreased GSH-Px mRNA expression and activity in liver and testis. The changes of TR mRNA level and activity in the liver and kidney were similar to those of GSH-Px in the liver and testis when supplemented with 40 and 80 microg Se/kg/d. There were no significant effects of Se status on kidney GSH-Px and testis TR expressions. The results suggested that Se overexposure had an adverse effect on GSH-Px and TR mRNA levels and activities, and there could be tissue differences in the regulation of selenoprotein levels.Biological Trace Element Research 12/2002; 89(2):165-75. · 1.31 Impact Factor
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ABSTRACT: As an experimental analogue of human focal glomerular sclerosis (FGS), adriamycin (ADR)-induced nephropathy is well-characterized in rats. Previously, this model has not been fully established in mice. The extension of this model to the mouse would be useful in the application of genetic and monoclonal antibody technology to characterize mechanisms of progressive renal disease. Herein, we describe a stable and reproducible murine model of chronic proteinuria induced by ADR. Male BALB/c mice were intravenously injected with a single dose of ADR (10 to 11 mg/kg). Seven mice were sacrificed at weeks 1, 2, 4, and 6. Renal function, quantitative morphometric analysis, and electron microscopic studies were performed. Peripheral CD4+ and CD8+ T cells were evaluated using flow cytometric analysis of splenocytes. The leukocytic inflammatory pattern was analyzed by immunohistochemical examination. Overt proteinuria was observed from day 5 and remained significantly elevated throughout the study period. A focal increase in reabsorption droplets in tubular cells appeared at weeks 1 and 2, and numerous intraluminal casts were present after two weeks. Glomerular vacuolation and mild FGS appeared at week 4. At week 6, extensive focal and even global glomerular sclerosis, associated with moderate interstitial expansion and severe inflammation, were observed. A prominent macrophage infiltration appeared within both interstitium and glomeruli at week 2, followed by accumulation of both CD4+ and CD8+ T cells in interstitium but not glomeruli. There were almost no B lymphocytes seen at any time. This model should be useful in unraveling the pathogenesis of glomerular and interstitial inflammation and fibrosis in chronic proteinuric renal disease.Kidney International 11/2000; 58(4):1797-804. · 7.92 Impact Factor
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ABSTRACT: Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.AJP Heart and Circulatory Physiology 02/2009; 296(3):H823-32. · 3.63 Impact Factor