Melatonin: an antioxidant protects against cyclosporine-induced nephrotoxicity

BACKGROUND: Cyclosporine (CsA) causes a dose-related decrease in renal function in experimental animals. Different mediators for CsA nephrotoxicity have been suggested; oxygen free radicals are one of them. In experimental model of Wistar rats, the role of antioxidant melatonin (Mel), the main product of pineal secretion, was investigated in CsA nephrotoxicity. METHODS: Male Wistar rats were divided into four groups: saline control, 50 mg/kg CsA, 500 microg/kg Mel, and CsA + Mel. At the end of 14th day of treatment, blood urea, creatinine, malondialdehyde, and creatinine and lithium clearance were estimated. Histopathological examination of kidney from all the groups was performed. RESULTS: CsA caused marked elevation in blood urea, serum creatinine, and plasma malondialdehyde and a decrease in creatinine and lithium clearance. Mel significantly antagonized CsA-induced renal impairment. Microcalcification in corticomedullary junction seen with CsA was prevented by Mel. CONCLUSION: These results indicate that Mel, through its antioxidant properties, provides protection against CsA-induced nephrotoxicity.     

Nigella sativa oil for prevention of chronic cyclosporine nephrotoxicity: an experimental model

Nephrotoxicity is the main secondary effect of cyclosporine A (CsA) treatment. The antioxidant action of Nigella sativa oil (NSO) may explain the protective effect of these agents against various hepatotoxic and nephrotoxic models in vivo and in vitro. This study was designed to investigate the possible protective effects of NSO, in prevention of chronic CsA-induced nephrotoxicity in rats. Animals were randomly divided into four experimental groups: the control group received sunflower oil, the other groups were treated with CsA (25 mg/kg/day b.w. orally) or NSO (2 ml/kg orally) or CsA + NSO, respectively. Urine and serum creatinine levels, tissue superoxide dismutase, glutathione peroxidase and catalase enzyme activities, and nitric oxide and malondialdehyde levels were measured, and histological examination was performed. In our study, CsA caused a significant deterioration in the renal function, morphology and gave rise to severe oxidative stress in the kidney. NSO significantly improved the functional and histological parameters and attenuated the oxidative stress induced by CsA. In conclusion, our study demonstrated for the first time that NSO protects kidney tissue against oxygen free radicals, preventing renal dysfunction and morphological abnormalities associated with chronic CsA administration.     

Direct effect of chronic cyclosporine treatment on collagen III mRNA expression and deposition in rat kidneys

BACKGROUND: It is hypothesized that in acute and chronic CsA nephrotoxicity, in vivo models CsA side-effects are mediated by Renin-Angiotensin II (RAS)-TGF-beta-1 pathway. However, to induce chronic nephrotoxicity, CsA administration has to be combined with a low salt diet, which causes hemodynamic changes and RAS up-regulation. MATERIALS AND METHODS: In order to define any direct correlation between CsA and nephrotoxicity, we studied in normal sodium fed rats, the chronic effects of CsA administration (group-1 treated with 12.5 mg/Kg/day of CsA subcutaneously; group 2 received daily placebo; group 3 interrupted CsA injection after 60 days), on renal TGF-beta-1 and collagen III expression, and on TGF-beta-1, collagen III and IV deposition. Sacrifices were performed after 2, 4, 8 and 12 weeks (wks) and kidneys were harvested for immunohistological studies and RT/PCR analysis. RESULTS: No difference of TGF-beta-1 expression and deposition was found among groups. Starting from the 2nd week of treatment, an increased collagen III deposition was evident in vessels and in outer medulla with subsequent extension at the 4th week to medullary rays and to cortex interstitium. The deposition paralleled the renal collagen III mRNA up-regulation: it was significantly higher in group 1 than in group 2 (p < 0.009 at 2nd wk; p < 0.016 at 4th wk). Collagen IV deposition did not differ between groups at any point. CONCLUSIONS: Our results suggest that chronic CsA administration can induce, in normal fed rats, the process of interstitial fibrogenesis through TGF-beta non-related mechanisms.     

Methotrexate causes oxidative stress in rat kidney tissues

AIM: Methotrexate (MTX), a folic acid antagonist, is one of the chemotherapeutic agents widely used in the treatment of some types of cancers. Nephrotoxicity is one of the complications of MTX treatment. The aim of this study was to investigate possible effects of MTX treatment on the oxidant/antioxidant status in rat kidney tissues and enzymatic mechanisms leading to nephrotoxicity. METHODS: For this aim, 10 Sprague-Dawley type female rats of 4 weeks old were used in the study. The animals were divided into two groups randomly. Five of them were used as control, and the others were treated with MTX intravenously (60 mg/m2 of body surface area per week) for 7 weeks. At the end of this period, they were sacrificed, and kidney tissues were removed to be used in the analyses of malondialdehyde (MDA) levels, antioxidant potential (AOP) values, and superoxide dismutase, catalase, glutathione peroxidase, xanthine oxidase, adenosine deaminase, and 5' nucleotidase enzyme activities. RESULTS: There was significant increase in the MDA level in the MTX group compared with the control group (1.74+/-0.23 nmol/mg vs. 1.04+/-0.30 nmol/mg; p<0.05, respectively). There were however no meaningful differences between enzyme activities and AOP values of the groups. CONCLUSION: It has been suggested that MTX leads to oxidative stress in rat kidney tissues, which might be one of the reasons for MTX-induced nephrotoxicity.     

N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats.

BACKGROUND: Cyclosporin (CsA) has played an important role in the improvement of solid-organ transplant patients and graft survival. However, nephrotoxicity due to CsA remains an important clinical challenge. The renal toxicity of CsA is attributed to reduced renal blood flow which leads to hypoxia reoxygenation injury accompanied by excessive generation of oxygen-derived free radicals (ODFR). N-acetyl-L-cysteine (NAC) is a highly potent antioxidant that has been shown to reduce ODFR injury. In this study an attempt was made to assess the effect of NAC on CsA-induced lipid peroxidation and nephrotoxicity. METHODS: Adult Sprague-Dawley rats were treated orally with CsA (25 and 50 mg/kg) alone and in combination with different doses of NAC (10, 20 and 40 mg/kg) for a period of 3 weeks. Twenty-four hours after the last treatment, animals were sacrificed and blood was analysed for blood urea nitrogen (BUN) and serum creatinine (SCr), and kidney samples were analysed for lipid hydroperoxides, conjugated dienes and glutathione, and histopathological changes. RESULTS: Treatment of rats with CsA produced a significant increase in BUN and SCr level and histological abnormalities. CsA-induced impairment of renal toxicity was accompanied by significant increase in renal oxidative stress. NAC treatment significantly protected animals against CsA-induced structural and functional impairment of kidney. CONCLUSIONS: CsA-induced nephrotoxicity was significantly attenuated by NAC. This study clearly suggests the role of oxidative stress in the pathogenesis of CsA-induced nephrotoxicity. Concomitant use of antioxidants such as NAC to minimize CsA-induced nephrotoxicity in humans warrant further studies.     

Protective effect of docosahexaenoic acid against cyclosporine A-induced nephrotoxicity in rats: a possible mechanism of action

The aim of this experimental study was to investigate whether, and how then, docosahexaenoic acid (DHA) could alleviate the cyclosporine A (CsA)-induced nephrotoxicity. Three main groups of Sprague-Dawley rats were treated orally with CsA (25 mg/kg), DHA (100 mg/kg), and CsA along with DHA. A corresponding control group was also used. DHA administration significantly reduced CsA-induced nephrotoxicity and associated hyperlipidemia and proteinuria as assessed by estimating serum triacylglycerol, serum total cholesterol, serum total protein, serum urea, and creatinine clearance. Furthermore, urinary excretions of protein and N-acetyl-β-D-glucosaminidase were significantly inhibited following DHA administration. DHA supplementation slightly attenuated the oxidative damage in kidney tissues as evaluated by the levels of thiobarbituric acid-reacting substances and protein carbonyl content in the kidney homogenate, although there were no significant differences between CsA-intoxicated and DHA-treated animals. Moreover, DHA treatment significantly restored total nitric oxide (NO) levels in both renal tissues and urine. This study demonstrates the ability of DHA to ameliorate CsA-induced renal dysfunction, which might be beneficial to enhance the therapeutic index of CsA. The data suggest that the protective potential of DHA in the prevention of CsA nephrotoxicity in rats was mainly associated with the increase of total NO bioavailability in renal tissues. Nevertheless, the exact independent mechanism in which DHA exerts its beneficial effect is yet to be fully elucidated.     

Mercury exacerbates cyclosporin nephrotoxicity in rats

Background The use of cyclosporin (CsA) in the presence of other nephrotoxic drugs poses a great challenge to physicians. This study was designed to address the effect of concomitant administration of mercury and cyclosporin on nephrotoxicity of rats. Methods Male Sprague-Dawley rats (weighing 230±20 g) were divided into the following 8 groups of 7 animals each: group 1, control; group 2, mercury alone; group 3, cyclosporin 12.5 mg/kg; group 4, cyclosporin 25 mg/kg; group 5, CsA 50 mg/kg; group 6, CsA 12.5 mg/kg+mercury; group 7, CsA 25 mg/kg+mercury; and group 8, CsA 50 mg/kg+mercury. Mercury (1 mg/kg) was given by subcutaneous injection, and CsA, by oral gavage; drugs were given once a day for 7 days. Twenty-four hours after the last dose of drugs, the animals were killed, and blood samples were assayed for BUN, serum creatinine, and CsA levels. The left kidney was analyzed for malondialdehyde, lipid hydroperoxides, vitamin E, and glutathione levels, and histopathologic analysis was done on the right kidney. Results Mercury significantly exacerbated CsA-induced nephrotoxicity. There was a highly significant increase in oxidative stress in animals treated with the combination of CsA and mercury. Mercury also increased the bioavailability of CsA in rats. Conclusions Concomitant treatment of mercury with CsA produced severe nephrotoxicity. The enhanced nephrotoxicity may be attributed to the increased bioavailability of CsA and an increase in lipid peroxidation after concomitant use of these drugs.     

Attenuation of Cyclosporine-Induced Renal Dysfunction by Catechin: Possible Antioxidant Mechanism

One of great use of immunosuppressant, Cyclosporine-A (CsA) is in the solid organ transplantation; however the extensive use of this is cautionable due to its toxic effect in renal tissue, characterized by the tubular atrophy, interstitial fibrosis, and progressive renal impairment. However, there are many mediators are associated with pathogenesis of nephrotoxicity of CsA, the exact mechanism is still in debate. Recent studies indicate that Reactive Oxygen Species (ROS) induced oxidative stress and lipid peroxidations are the important mechanisms implicated in the pathophysiology of nephrotoxicity with CsA. In the present study we examined effect of dietary flavonoid catechin on oxidative damage in cyclosporine-A induced nephrotoxicity. Chronic administration of CsA (20 mg/kg/day) subcutaneously for 21 days significantly decreased the body weight as compared with vehicle treated rats. CsA (20 mg/kg/day) administration for 21 days significantly decreased the renal function by increase in the serum creatinine, blood urea nitrogen, and decrease in the creatinine and urea clearance as compared with vehicle treated rats. Catechin (100 mg/kg/day) for 21 days along with CsA significantly reversed the changed renal parameters, however lower dose of catechin (50 mg/kg/day) restored only increased serum creatinine levels as compared with CsA alone treated group. Biochemical analysis revealed that chronic administration of CsA (20 mg/kg/day) for 21 days significantly induced lipid peroxidation and decreased the glutathione levels in the kidney homogenate of rats. It is also observed that chronic CsA administered rats showed decrease in antioxidant defense enzyme superoxide dismutase and increase in the catalase activity as compared with vehicle treated rats. Co-administration of catechin (100 mg/kg/day) orally along with CsA for 21 days significantly reduced the lipid peroxidation and restored the decreased glutathione levels as compared with CsA alone group, but lower dose of catechin (50 mg/kg/day) restored only decreased glutathione levels induced by CsA. Co-administration of only higher dose of catechin (100 mg/kg/day) along with CsA significantly increased the superoxide dismutase (SOD) levels as compared with CsA alone treated group. It is also observed that catechin (100 mg/kg/day) along with CsA further increased the catalase levels as compared with CsA alone treated group, but not with lower dose of catechin. Animals administered with catechin (100 mg/kg/day) alone for 21 days showed significant increase in the catalase levels as compared with vehicle treated group. The major findings of the present study suggest that oxidative stress might play a significant role in CsA-induced nephrotoxicity. In conclusion, dietary administration of flavonoid catechin could be a useful component for the prevention/treatment of CsA-induced nephrotoxicity.     

Attenuation of cyclosporine-induced renal dysfunction by catechin: possible antioxidant mechanism

One of great use of immunosuppressant, Cyclosporine-A (CsA) is in the solid organ transplantation; however the extensive use of this is cautionable due to its toxic effect in renal tissue, characterized by the tubular atrophy, interstitial fibrosis, and progressive renal impairment. However, there are many mediators are associated with pathogenesis of nephrotoxicity of CsA, the exact mechanism is still in debate. Recent studies indicate that Reactive Oxygen Species (ROS) induced oxidative stress and lipid peroxidations are the important mechanisms implicated in the pathophysiology of nephrotoxicity with CsA. In the present study we examined effect of dietary flavonoid catechin on oxidative damage in cyclosporine-A induced nephrotoxicity. Chronic administration of CsA (20 mg/kg/day) subcutaneously for 21 days significantly decreased the body weight as compared with vehicle treated rats. CsA (20 mg/kg/day) administration for 21 days significantly decreased the renal function by increase in the serum creatinine, blood urea nitrogen, and decrease in the creatinine and urea clearance as compared with vehicle treated rats. Catechin (100 mg/kg/day) for 21 days along with CsA significantly reversed the changed renal parameters, however lower dose of catechin (50 mg/kg/day) restored only increased serum creatinine levels as compared with CsA alone treated group. Biochemical analysis revealed that chronic administration of CsA (20 mg/kg/day) for 21 days significantly induced lipid peroxidation and decreased the glutathione levels in the kidney homogenate of rats. It is also observed that chronic CsA administered rats showed decrease in antioxidant defense enzyme superoxide dismutase and increase in the catalase activity as compared with vehicle treated rats. Co-administration of catechin (100 mg/kg/day) orally along with CsA for 21 days significantly reduced the lipid peroxidation and restored the decreased glutathione levels as compared with CsA alone group, but lower dose of catechin (50 mg/kg/day) restored only decreased glutathione levels induced by CsA. Co-administration of only higher dose of catechin (100 mg/kg/day) along with CsA significantly increased the superoxide dismutase (SOD) levels as compared with CsA alone treated group. It is also observed that catechin (100 mg/kg/day) along with CsA further increased the catalase levels as compared with CsA alone treated group, but not with lower dose of catechin. Animals administered with catechin (100 mg/kg/day) alone for 21 days showed significant increase in the catalase levels as compared with vehicle treated group. The major findings of the present study suggest that oxidative stress might play a significant role in CsA-induced nephrotoxicity. In conclusion, dietary administration of flavonoid catechin could be a useful component for the prevention/treatment of CsA-induced nephrotoxicity.     

Protective Effect of Docosahexaenoic Acid Against Cyclosporine A-Induced Nephrotoxicity in Rats: A Possible Mechanism of Action

The aim of this experimental study was to investigate whether, and how then, docosahexaenoic acid (DHA) could alleviate the cyclosporine A (CsA)-induced nephrotoxicity. Three main groups of Sprague–Dawley rats were treated orally with CsA (25 mg/kg), DHA (100 mg/kg), and CsA along with DHA. A corresponding control group was also used. DHA administration significantly reduced CsA-induced nephrotoxicity and associated hyperlipidemia and proteinuria as assessed by estimating serum triacylglycerol, serum total cholesterol, serum total protein, serum urea, and creatinine clearance. Furthermore, urinary excretions of protein and N-acetyl-β-d-glucosaminidase were significantly inhibited following DHA administration. DHA supplementation slightly attenuated the oxidative damage in kidney tissues as evaluated by the levels of thiobarbituric acid-reacting substances and protein carbonyl content in the kidney homogenate, although there were no significant differences between CsA-intoxicated and DHA-treated animals. Moreover, DHA treatment significantly restored total nitric oxide (NO) levels in both renal tissues and urine. This study demonstrates the ability of DHA to ameliorate CsA-induced renal dysfunction, which might be beneficial to enhance the therapeutic index of CsA. The data suggest that the protective potential of DHA in the prevention of CsA nephrotoxicity in rats was mainly associated with the increase of total NO bioavailability in renal tissues. Nevertheless, the exact independent mechanism in which DHA exerts its beneficial effect is yet to be fully elucidated.     

Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity

Previous reports suggest that cyclosporine (CsA) may have direct effects on arachidonic acid (AA) metabolism in several different tissues. However, the effects of CsA on renal eicosanoid production are unclear. Furthermore, the potential role of changes in renal prostaglandin and thromboxane metabolism in mediating CsA nephrotoxicity is not known. Therefore, in this study, we evaluated the effects of CsA toxicity on the production of AA metabolites by the kidney. In a postischemic, denervated rat model, CsA (50 mg/kg/day) administered for 12-14 days resulted in significant nephrotoxicity with marked decreases in both glomerular filtration rate and renal blood flow. This reduction in renal function was associated with an increase in the renal production of TXB2, PGE2, and 6-PGF1 alpha in vitro. Arachidonic acid significantly stimulated renal eicosanoid production above control values. Increased urinary excretion of TXB2, 2,3-dinorTXB2 (a major TXB2 metabolite), and 6-keto-PGF1 alpha also occurred in rats with CsA nephrotoxicity and reflected the increase in renal production of these eicosanoid products. In contrast, urinary PGE2 excretion was not increased in CsA toxic rats. Thus, CsA nephrotoxicity is associated with specific alterations in renal AA metabolism. Furthermore, alterations in AA metabolism may be important in modulating renal hemodynamics and excretory function in this model. These studies suggest that specific inhibition of vasoconstrictor products of AA metabolism might ameliorate the nephrotoxic effects of CsA.     

In vivo effect of the natural antioxidant hydroxytyrosol on cyclosporine nephrotoxicity in rats.

BACKGROUND: Cyclosporine A (CsA) is the first-line immunosuppressant used in transplant patients and in auto- immune diseases. Nephrotoxicity is the major limitation of CsA use. Although the mechanisms of nephrotoxicity have not been completely defined, some evidence suggests that reactive oxygen species (ROS) play a causal role. The present study was designed to investigate in vivo effects of hydroxytyrosol (DOPET), a natural olive oil antioxidant, on oxidative stress, renal histology and haemodynamic alterations induced in rats by CsA treatment. METHODS: Adult Sprague-Dawley rats were treated i.p. with CsA (15 mg/kg) alone or in combination with DOPET (20 mg/kg) for 3 weeks. At the end of the treatment, superoxide concentration within the cells of the abdominal aorta and renal artery was quantified from the oxidation of dihydroethidium (DHE) using fluorescence microscopic imaging analysis. In kidney tissues, lipid peroxidation was measured by thiobarbituric acid-reacting substances (TBARS) assay, glutathione level was assessed enzymatically and the expression of haem oxygenase-1 (HO-1) gene was evaluated by semiquantitative RT-PCR. Renal morphology was studied by classical histological techniques, while the glomerular filtration rate (GFR) was estimated by inulin clearance. Systemic blood pressure was monitored by the tail method and through the catheterization of the carotid artery. RESULTS: CsA administration increased superoxide concentration both in the aorta and in the renal artery, while DOPET completely prevented this effect. Higher levels of TBARS, a significant decrease in GSH and an upregulation of HO-1 mRNA were observed in the kidneys of CsA-treated rats. DOPET treatment reversed quantitatively these effects. However, CsA-dependent changes in renal histology were only partially reversed by DOPET. Finally, CsA induced a severe reduction in GFR and a significant increase in both systolic and diastolic blood pressure; the DOPET treatment had no significant effect on these haemodynamic alterations. CONCLUSION: The reported data indicate that effective DOPET protection from CsA-induced oxidative stress is associated with a mild effect on histological damages and does not affect the altered glomerular function and the hypertension, thus indicating that kidney injury by CsA is only in part dependent on oxidative stress.     

Effect of Bicarbonate Administration on Cyclosporine-Induced Nephrotoxicity in Rats

Background

Cyclosporine (CsA) is known to cause metabolic and distal tubular acidosis. There is some evidence that CsA reduces net HCO₃⁻ absorption. The aim of this study was to elucidate whether bicarbonate administration prevented CsA-induced functional or structural nephrotoxicity.

Methods

Seven days after uninephrectomy, 20 rats were divided into 4 groups. NaHCO₃ (0.28 mol/L) was added in drinking water for 7 days, whereas control rats received regular tap water. The bicarbonate pretreated rats were administered either CsA (50 mg/kg intraperitoneally) or vehicle daily for a week. At the end of the procedure, animals were placed in metabolic cages for 24 hours after which we measured creatinine clearance (Ccr), urinary total proteins, pH, and N-acetyl-β-D-glucosaminidase (NAG) activity. The kidney was fixed in formaldehyde.

Results

Ccr was significantly affected by the administration of CsA. The effects of CsA on serum pH and HCO₃⁻ concentration were prevented by pretreatment with NaHCO₃. However, it did not affect the CsA-induced increased urinary NAG activity or decreased Ccr. There was no protection of CsA-induced changes in renal tissues by NaHCO₃.

Conclusion

Overall NaHCO₃ administration did not prevent CsA-induced changes in Ccr and NAG activity. These data suggested involvement of factors other than acid-base status in CsA-induced nephrotoxicity. However, correction of acidosis should still be considered for patients receiving CsA because acidosis exacerbates tissue damage.     

Methotrexate Causes Oxidative Stress in Rat Kidney Tissues

Aim. Methotrexate (MTX), a folic acid antagonist, is one of the chemotherapeutic agents widely used in the treatment of some types of cancers. Nephrotoxicity is one of the complications of MTX treatment. The aim of this study was to investigate possible effects of MTX treatment on the oxidant/antioxidant status in rat kidney tissues and enzymatic mechanisms leading to nephrotoxicity. Methods. For this aim, 10 Sprague-Dawley type female rats of 4 weeks old were used in the study. The animals were divided into two groups randomly. Five of them were used as control, and the others were treated with MTX intravenously (60 mg/m² of body surface area per week) for 7 weeks. At the end of this period, they were sacrificed, and kidney tissues were removed to be used in the analyses of malondialdehyde (MDA) levels, antioxidant potential (AOP) values, and superoxide dismutase, catalase, glutathione peroxidase, xanthine oxidase, adenosine deaminase, and 5′ nucleotidase enzyme activities. Results. There was significant increase in the MDA level in the MTX group compared with the control group (1.74 ± 0.23 nmol/mg vs. 1.04 ± 0.30 nmol/mg; p < 0.05, respectively). There were however no meaningful differences between enzyme activities and AOP values of the groups. Conclusion. It has been suggested that MTX leads to oxidative stress in rat kidney tissues, which might be one of the reasons for MTX-induced nephrotoxicity.     

环孢霉素A肾毒性的发病机制及人参总皂甙的预防作用

环孢霉素Ａ（ＣｓＡ）肾毒性的作用机理至今不十分明确，而反应性氧代谢产物（ＲＯＭ）与许多肾脏疾病有关。将Ｗｉｓｔａｒ大鼠分别给ＣｓＡ三种剂量１２．５、２５、５０ｍｇ·ｋｇ－１／ｄ日灌胃７天，大鼠出现急性肾功能不全，血肌酥、血清及肾皮质匀浆丙二醛显著升高，而肾皮质匀浆超氧化物歧化酶活性及全血谷胱甘肽过氧化物酶活性下降。在人参总皂甙及去铁敏预防组中，上述指标与正常组无显著差异，提示ＲＯＭ产生的增加及肾脏抗氧化能力的下降参与了ＣｓＡ所致的急性肾毒性，而入参总皂甙、去铁敏具有预防作用。     

Caffeic Acid Phenethyl Ester Protects Kidneys against Acetylsalicylic Acid Toxicity in Rats

Aim: The aim of this study was to investigate the protective effect of caffeic acid phenethyl ester (CAPE) on acetylsalicylic acid (ASA)-induced renal damage in rats. Materials and methods: A total of 40 rats were randomly divided into five groups, with eight rats in each group—group 1: control, not receiving any medication; group 2: ASA (50 mg/kg/day); group 3: ASA (50 mg/kg/day) + CAPE (20 μg/kg/day); group 4: ASA (100 mg/kg/day); and group 5: ASA (100 mg/kg/day) + CAPE (20 μg/kg/day). ASA and CAPE were given via orogastric gavage for 5 days. The total oxidant status (TOS), total antioxidant capacity (TAC), and paraoxonase-1 (PON-1) activity of the blood samples and kidney tissues were determined. Histopathological examinations of the kidneys were performed using light microscopic methods. Results: The TOS level in the serum of rats and kidney tissues given ASA (groups 2 and 4) significantly increased, but the levels of TAC and PON-1 in these tissues significantly decreased in group 4 when compared with the control rats (p < 0.05). The levels of TAC and PON-1 in the kidney tissues increased and the levels of TOS decreased in the CAPE treatment groups (groups 3 and 5) when compared with the rats in the no CAPE treatment groups (groups 2 and 4). The PON-1, TAC, and TOS values reverted to normal levels in group 5 when compared to group 4 (p < 0.05). These results were supported by histopathological observation. Conclusion: Oxidative stress plays an important role in ASA-induced nephrotoxicity, and CAPE may protect against ASA-induced nephrotoxicity in rats.     

Viral delivery of superoxide dismutase gene reduces cyclosporine A-induced nephrotoxicity

BACKGROUND: Cyclosporine A (CsA) increases free radical formation in the kidney. Accordingly, this study investigated whether gene delivery of superoxide dismutase (SOD) reduced radical production and nephrotoxicity caused by CsA. METHODS: Rats were given adenovirus (Ad) carrying lacZ or Cu/Zn-SOD genes three days prior to CsA treatment. Histology, glomerular filtration rates (GFRs) and free radical adducts in urine were assessed. RESULTS: SOD activity was increased 2.5-fold three days after viral infection and remained at 2- and 1.6-fold higher 10 and 17 days later. Treatment with CsA for seven days decreased GFR by 70% in rats infected with Ad-lacZ as expected; however, the decrease was diminished significantly in rats receiving Ad-SOD. CsA treatment for two weeks caused a loss of brush border and dilation of proximal tubules, necrosis, and increased leukocyte infiltration into the kidney; these effects were minimized by SOD. Dimethyl sulfoxide (DMSO) was attacked by the hydroxyl radical to produce a methyl radical. Indeed, administration of CsA with 12C-DMSO in rats infected with Ad-lacZ produced a radical adduct with hyperfine coupling constants similar to 4-POBN/methyl radical adduct and another unknown radical adduct. CsA given with 13C-DMSO produced a 12-line spectrum, confirming the involvement of hydroxyl radicals. Free radical adducts detected in urine were increased approximately fivefold by CsA, an effect blocked completely by SOD. CONCLUSIONS: CsA increases free radical formation. Gene delivery of SOD blocks formation of free radicals, thereby minimizing nephrotoxicity caused by CsA.     

Whortleberry protects kidney against the cisplatin-induced nephrotoxicity: an experimental study

Purpose: This study investigated the antioxidant effects of whortleberry against cisplatin-induced nephrotoxicity in rats.

Material and methods: This study included 48 female Sprague–Dawley rats weighing 263.68?±?8.29?g. The rats were divided into the following six groups, with eight rats in each group: control, ethanol control, whortleberry control, cisplatin control, 16?mg/kg cisplatin +100?mg/kg whortleberry, and 16?mg/kg cisplatin +200?mg/kg whortleberry groups. Biochemical analysis was performed by measuring total oxidant status and total antioxidant status, histopathological analysis was performed by calculating proximal and distal tubule areas (μm²), and immunohistochemical analysis was performed by determining anti-Caspase-3 immunostaining. Differences among the groups were examined using one-way analysis of variance, and p?Results: Cisplatin treatment decreased the total antioxidant status and increased the total oxidant status and Caspase-3 level. Moreover, it resulted in the dilatation, vacuolization and loss of tubular epithelial cells; and glomerular degeneration and edema in the kidney tissues (p?p?Conclusions: Our results indicate that the antioxidant effects of the whortleberry decrease cisplatin-associated nephrotoxicity.     

Oxidative stress in cyclosporine-induced hypertension: evidence of beneficial effects or tolerance development with nitrate therapy

The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n = 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn + CsA therapy showed, when compared with the CsA group, total prevention of CsA-induced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA + Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 +/- 1.4 vs 12.78 +/- 3.63 mumol/L; P < .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.     

Colchicine suppresses osteopontin expression and inflammatory cell infiltration in chronic cyclosporine nephrotoxicity

BACKGROUND: Colchicine (Col) is beneficial to renal injury because of its anti-inflammatory effect, but its mechanism has yet to be elucidated. The present study was designed to evaluate the inhibitory effects of colchicine on osteopontin (OPN) expression and the macrophage accumulation in chronic cyclosporine (CsA) nephrotoxicity in rats. METHODS: Male adult Sprague-Dawley rats on a low salt diet (LSD, 0.05% sodium) were treated daily with Col (30 microg/kg), CsA (15 mg/kg), and both CsA and colchicine or vehicle (olive oil 1 ml/kg) for 4 weeks. The effects of colchicine on chronic CsA nephrotoxicity were evaluated by examining renal function, histopathology, and ED-1 positive cells. The expressions of OPN mRNA and protein were estimated respectively by Northern blot and immunohistochemistry. RESULTS: Compared with vehicle-treated rats, CsA-treated rats showed an increase in serum creatinine, a decline in creatinine clearance rate, and tubulointerstitial fibrosis (all p < 0.01). Concomitant administration of colchicine reversed all of the above parameters (all p < 0.01). Of note, the upregulated expression of osteopontin mRNA and protein seen in CsA-treated rats was significantly decreased after colchicine treatment. Furthermore, the expression of osteopontin mRNA was strongly correlated with the number of ED-1 positive cells (r = 0.712, p < 0.001) and the tubulointerstitial fibrosis score (r = 0.586, p = 0.007). CONCLUSION: Colchicine is capable of abrogating the upregulation of chemotactic OPN expression and macrophage influx, and this is associated with improved renal tubulointerstitial fibrosis in chronic CsA nephrotoxicity.