Oxidative stress and kidney dysfunction due to ischemia/reperfusion in rat: Attenuation by dehydroepiandrosterone

Males are much more susceptible to ischemia/reperfusion (I/R)-induced kidney injury when compared with females. Recently we reported that the presence of testosterone, rather than the absence of estrogen, plays a critical role in gender differences in kidney susceptibility to I/R injury in mice. Although reactive oxygen species and antioxidant defenses have been implicated in I/R injury, their roles remain to be defined. Here we report that the orchiectomized animal had significantly less lipid peroxidation and lower hydrogen peroxide levels in the kidney 4 and 24 h after 30 min of bilateral renal ischemia when compared with intact or dihydrotestosterone-treated orchiectomized males. The post-ischemic kidney expression and activity of manganese superoxide dismutase (MnSOD) in orchiectomized mice was much greater than in intact or dihydrotestosterone-administered orchiectomized mice. Four hours after 30 min of bilateral ischemia, superoxide formation was significantly lower in orchiectomized mice than in intact mice. In Madin-Darby canine kidney cells, a kidney epithelial cell line, 1 mM H 2 O 2 decreased MnSOD activity, an effect that was potentiated by pretreatment with dihydrotestosterone. Orchiectomy prevented the post-ischemic decrease of catalase activity. Treatment of male mice with manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a SOD mimetic, reduced the post-ischemic increase of plasma creatinine, lipid peroxidation, and tissue hydrogen peroxide. These results suggest that orchiectomy accelerates the post-ischemic activation of MnSOD and reduces reactive oxygen species and lipid peroxidation, resulting in reduced kidney susceptibility to I/R injury.Gender differences in disease susceptibility have been well characterized in many cardiovascular diseases (1-3). The increased risk for cardiovascular diseases in men and postmenopausal women (4) has been attributed primarily to lack of estrogen-mediated protection (5-7). Recently we demonstrated that male mice are much more susceptible to kidney ischemia/reperfusion (I/R) 5 injury when compared with female mice (8), and that orchiectomy decreases kidney susceptibility to I/R injury (9), whereas ovariectomy has no effect on kidney susceptibility to I/R injury (8). Testosterone administration to orchiectomized male or female mice reverses the protective phenotype, increasing susceptibility to kidney I/R injury. We concluded that the presence of testosterone, rather than the absence of estrogen, plays a critical role in the gender differences in kidney susceptibility to I/R injury. The detailed molecular mechanisms responsible for this testosterone effect remain to be defined.Ischemia/reperfusion markedly increases the production of reactive oxygen species (ROS) including superoxide anions, hydroxyl radicals, hypochlorous acid, hydrogen peroxide, and peroxynitrite (10). The abnormal excessive production of ROS results in lipid peroxidation, leukocyte activation, endothelial cell damage, and cytokine production, all of which contribute to tissue ...

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“…Excessive ROS production is an important cause of I/Rinduced injury (11,32). ROS have been implicated in gender FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

Orchiectomy Attenuates Post-ischemic Oxidative Stress and Ischemia/Reperfusion Injury in Mice

Kim

Kil

Seok

et al. 2006

Journal of Biological Chemistry

115

116

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“…Nitric oxide has been found to be directly toxic in isolated rat proximal tubule segments exposed to hypoxia and reoxygenation and high levels of nitric oxide have also been observed in several renal dysfunction models. 57 The deleterious effect of increased nitric oxide in reperfused kidney might be greatly enhanced by a simultaneous increase in superoxide radicals. In the presence of superoxide, NO interacts with superoxide to form peroxynitrate radicals, an important agent that can cause oxidative and DNA damage.…”

confidence: 99%

Prevention of renal ischemia/reperfusion‐induced injury in rats by leflunomide

Karaman

Türkmen²,

Gürsul

et al. 2006

Int J of Urology

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Objective: There is increasing evidence to suggest that toxic oxygen radicals play an essential role in the pathogenesis of ischemia/ reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of leflunomide, an isoxazole derivative and a unique immunomodulatory agent, in I/R-induced renal injury in rats. Methods: Forty female Sprague-Dawley rats were divided equally into four groups: (I) control (only leflunomide 10 mg/kg, intragastrically treated); (II) sham operated (only unilateral nephrectomy); (III) I/R; and (IV) leflunomide (10 mg/kg for two doses prior to experiment) plus I/R groups. In groups III and IV, after unilateral nephrectomy, the rats were subjected to 60 min of left renal pedicle occlusion, followed by 6 h of reperfusion. At the end of the reperfusion period, rats were killed and kidneys and blood were removed. Catalase, myeloperoxidase and xanthine oxidase activities, and malondialdehyde, nitric oxide and protein carbonyl levels were determined in renal tissue. Serum creatinine, blood urea nitrogen and aspartate aminotransferase were measured for the evaluation of renal function. In histopathological examination, renal damage was scored 0-3. Results: Group III animals demonstrated severe deterioration of renal function, renal morphology and a significant renal oxidative stress. Pretreatment of animals with leflunomide markedly attenuated renal dysfunction, morphological alterations, reduced elevated oxidative stress products levels and restored the depleted renal antioxidant enzyme. Conclusion:The findings imply that oxygen radicals play a causal role in I/R-induced renal injury, and leflunomide exerts renoprotective effects probably by the radical scavenging and antioxidant activities with immunomodulatory effect.

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“…Many metabolic effects, including antiobesity, antidiabetic, and antiaging properties, have been attributed to DHEA. 4 In rodents, DHEA attenuated ischemia/reperfusion-induced oxidative stress and renal dysfunction, 5 showed beneficial effects in diabetic nephropathy, 6,7 and inhibited the age-related development of proteinuria. 8 DHEA seems to counteract several adverse effects of excessive glucocorticoid action, including a negative correlation between DHEA concentrations and body mass index, visceral adiposity, and impaired insulin sensitivity in elderly individuals 9 ; however, the molecular mechanisms underlying these antiglucocorticoid effects remain unclear.…”

mentioning

confidence: 99%

DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins

Balázs

Schweizer²,

Frey³

et al. 2008

Journal of the American Society of Nephrology

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11␤-Hydroxysteroid dehydrogenase (11␤-HSD) type 1 and type 2 catalyze the interconversion of inactive and active glucocorticoids. Impaired regulation of these enzymes has been associated with obesity, diabetes, hypertension, and cardiovascular disease. Previous studies in animals and humans suggested that dehydroepiandrosterone (DHEA) has antiglucocorticoid effects, but the underlying mechanisms are unknown. In this study, DHEA treatment markedly increased mRNA expression and activity of 11␤-HSD2 in a rat cortical collecting duct cell line and in kidneys of C57BL/6J mice and Sprague-Dawley rats. DHEA-treated rats tended to have reduced urinary corticosterone to 11-dehydrocorticosterone ratios. It was found that CCAAT/enhancer-binding protein-␣ (C/EBP-␣) and C/EBP-␤ regulated HSD11B2 transcription and that DHEA likely modulated the transcription of 11␤-HSD2 in a phosphatidylinositol-3 kinase/Akt-dependent manner by increasing C/EBP-␤ mRNA and protein expression. Moreover, it is shown that C/EBP-␣ and C/EBP-␤ differentially regulate the expression of 11␤-HSD1 and 11␤-HSD2. In conclusion, DHEA induces a shift from 11␤-HSD1 to 11␤-HSD2 expression, increasing conversion from active to inactive glucocorticoids. This provides a possible explanation for the antiglucocorticoid effects of DHEA. Enhanced glucocorticoid effects, mainly as a result of locally disturbed glucocorticoid metabolism, contribute to diseases such as hypertension and the metabolic syndrome. 1-3 The adrenal steroid hormone precursor dehydroepiandrosterone (DHEA) is the most abundant circulating steroid in humans, with peak levels between 20 and 30 yr of age, followed by a steady, age-dependent decline. Many metabolic effects, including antiobesity, antidiabetic, and antiaging properties, have been attributed to DHEA. 4 In rodents, DHEA attenuated ischemia/reperfusion-induced oxidative stress and renal dysfunction, 5 showed beneficial effects in diabetic nephropathy, 6,7 and inhibited the age-related development of proteinuria. 8 DHEA seems to counteract several adverse effects of excessive glucocorticoid action, including a negative correlation between DHEA concentrations and body mass index, visceral adiposity, and impaired insulin sensitivity in elderly individuals 9 ; however, the molecular mechanisms underlying these antiglucocorticoid effects remain unclear.In peripheral tissues, local glucocorticoid metabolism is mainly controlled by 11␤-hydroxysteroid dehydrogenase (11␤-HSD1) and 11␤-HSD2. 11␤-HSD1 catalyzes the reduction of inactive 11-ketoglucocorticoids (cortisone, 11-dehydrocorticosterone) into active 11␤-hy-

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Oxidative stress and kidney dysfunction due to ischemia/reperfusion in rat: Attenuation by dehydroepiandrosterone

Cited by 96 publications

References 51 publications

Orchiectomy Attenuates Post-ischemic Oxidative Stress and Ischemia/Reperfusion Injury in Mice

Orchiectomy Attenuates Post-ischemic Oxidative Stress and Ischemia/Reperfusion Injury in Mice

Prevention of renal ischemia/reperfusion‐induced injury in rats by leflunomide

DHEA Induces 11β-HSD2 by Acting on CCAAT/Enhancer-Binding Proteins

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