Renal Glutathione Content Research Articles

Regulation of renal nitric oxide and eNOS/iNOS expression by tadalafil participates in the mitigation of amphotericin B–induced renal injury: Down-regulation of NF-κB/iNOS/caspase-3 signaling

Amphotericin B (AmB)–induced acute kidney injury (AKI) is a common health problem having an undesirable impact on its urgent therapeutic utility for fatal systemic fungal infections. Tadalafil (TAD), a phosphodiesterase-5 (PDE-5) inhibitor, has been observed to have a wide range of pharmacological actions, including nephroprotection. The study’s objective was to examine the possible underlying protective mechanism of TAD against AmB-induced nephrotoxicity. Experimentally, animals were divided randomly into four groups: control, TAD (5 mg/kg/day; p.o.), AmB (18.5 mg/kg/day; i.p.), and TAD+AmB groups. Sera and tissue samples were processed for biochemical, molecular, and histological analyses. The biochemical investigations showed that TAD significantly ameliorated the increase of kidney function biomarkers (creatinine, urea, CysC, KIM-1) in serum, renal nitric oxide (NO), lipid peroxidation (MDA), and inflammatory cytokines (TNF-α, IL-6) in AmB-treated rats. Meanwhile, TAD significantly retarded AmB-induced decrease in serum magnesium, sodium, potassium, and renal glutathione content. Molecular analysis revealed that TAD reduced AmB-induced imbalance in the protein expression of eNOS/iNOS, which explains its regulatory effect on renal NO content. These results were also supported by the down-regulation of nuclear NF-κB p65 and cleaved caspase-3 protein expressions, as well as the improvement of histological features by TAD in AmB-treated rats. Therefore, it can be suggested that TAD could be a promising candidate for renoprotection against AmB-induced AKI. That could be partly attributed to its regulatory effect on renal eNOS/iNOS balance and NO, the inhibition of NF-κB p65 nuclear translocation, its downstream inflammatory cytokines and iNOS, and ultimately the inhibition of caspase-3-induced renal apoptosis.

Supplementation of conventional anti-diabetic therapy with alpha-lipoic acid prevents early development and progression of diabetic nephropathy

BackgroundDiabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN. MethodFifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses. ResultInduction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained β-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p < 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1β and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p < 0.001). ConclusionALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.

Effects of fermented red bean extract on nephropathy in streptozocin-induced diabetic rats.

BackgroundThe antioxidant effects of Bacillus subtilis-fermented red bean (natto-red bean) extract (NRBE) in young (6 weeks old) Sprague–Dawley rats and aged (12 months old) mice had been reported previously.ObjectiveTo evaluate the antioxidant and anti-inflammatory effects of NRBE in the kidneys of streptozocin-induced diabetic rats.DesignNormal control rats and diabetic rats were orally gavaged with saline and low-dose NRBE (100 mg/kg body weight [BW]), medium-dose NRBE (200 mg/kg BW), and high-dose NRBE (500 mg/kg BW), for 12 weeks and then sacrificed. Concentration of fasting glucose, adiponectin, renal function markers, antioxidative markers, and pro-inflammatory markers were measured.ResultsOral administration of 50% ethanolic extract of NRBE with a dosage of 100 mg/kg BW, 200 mg/kg BW, or 500 mg/kg BW could improve the symptoms of kidney enlargement and renal function. Supplementation of NRBE can effectively inhibit the formation of renal reactive oxygen species and advanced-glycation end-products and increase renal glutathione content and serum adiponectin. A low dose of NRBE (100 mg/kg BW) decreased fasting blood sugar and renal interleukin (IL)-6 expression. Serum C-reactive protein, renal tumor necrosis factor-α, and monocyte chemoattractant protein-1 concentrations were decreased, and renal superoxide dismutase activity was increased in the medium-dose NRBE group. Twenty-four hour creatinine clearance and urinary albumin excretion also improved by medium-dose NRBE supplementation. In NRBE, total phenols and flavonoids were 6.3 mg gallic acid equivalent/g and 12.02 mg rutin equivalent/g, respectively, and kampherol was the major active antioxidant compound.ConclusionThis study demonstrated that appropriate amount of NRBE, 200 mg/kg BW in rats, could prevent diabetic nephropathy by improving antioxidant status and inhibiting inflammation in renal tissue.

Influence of Spirulina platensis and ascorbic acid on amikacin-induced nephrotoxicity in rabbits.

The current study was performed to investigate the nephroprotective efficacy of Spirulina platensis (SP) and the possible benefits of combining SP and ascorbic acid (AA) in protecting against amikacin (AMK)-induced nephrotoxicity in rabbits. Forty-two male New Zealand rabbits were allocated to seven equal groups, receiving (I) normal saline as negative controls, (II) oral SP (500mg/kg body weight), (III) oral AA (20mg/kg bw), (IV) intramuscular AMK injection (100mg/kg bw), (V) AMK plus SP, (VI) AMK plus AA, or (VII) AMK plus SP and AA at the aforementioned doses. The treatments were given once/day for 7days. Data analysis showed that in comparison to the control group, AMK-intoxicated rabbits showed significant increases (p ≤ 0.05) in serum concentrations of creatinine, uric acid, and urea, as well as renal tissue concentrations of tumor necrosis factor-α [TNF-α], malondialdehyde [MDA], and nitric oxide [NO]. Moreover, significant (p ≤ 0.05) reductions in renal glutathione concentration, antioxidant enzymatic activities (catalase, glutathione peroxidase, and superoxide dismutase), and total antioxidant capacity were noted following AMK intoxication. Treatment by SP ameliorated most of the aforementioned AMK-induced alterations. Although treatment with AA significantly reduced the renal tissue MDA, NO, and TNF-α concentrations, it was not associated with significant ameliorations of AMK-induced changes in the serum concentrations of renal function markers or renal tissue antioxidant parameters. The nephroprotective effects of SP-AA combination were more potent than SP alone in several parameters. In conclusion, SP alone or in combination with AA minimized the nephrotoxic effects of AMK through their antioxidant and anti-inflammatory activities.

Antiapototic Effect of Captopril in Cisplatin - Induced Kidney Injury in Rats

Aim of the work: captopril protects against cisplatin induced nephrotoxicitity; however its potential modulatory effect on hemeoxygenase (HO)-1, antioxidants, as well as inflammatory and apoptotic markers has not yet been verified. Materials and methods: male Sprague-Dawley rats were divided into control (saline), cisplatin (5 mg/kg; i.p), and captopril (60 and 100 mg/kg) given 5 days before and after cisplatin (5 mg/kg; i.p) treatment. Results:five-day pre- and post-treatment with captopril (60 and 100 mg/kg; i.p), for a total of 10 days, dose dependently, reduced blood urea nitrogen, as well as serum creatinine and gamma glutamyl transferase, but serum albumin and total protein levels were increased. Captopril restored renal pro-oxidant/antioxidant balance by activating glutathione peroxidase, catalase and superoxide dismutase, and boosting the renal glutathione content. These effects were accompanied by the reduction in serum and/or renal HO-1, tumor necrosis factor-α, monocyte chemoattractant protein-1, nitric oxide, endothelin-1 and caspase-3. Microscopically, captopril especially at 100 mg/kg dose level, prevented cisplatin-induced degenerative changes and inflammatory cell infiltration in the kidney. Conclusion: captopril protects against cisplatin nephrotoxicity by its antioxidant, anti-inflammatory and antiapoptotic potentials.

Renoprotective Effect of Lactoferrin against Chromium-Induced Acute Kidney Injury in Rats: Involvement of IL-18 and IGF-1 Inhibition.

Hexavalent chromium (CrVI) is a heavy metal widely used in more than 50 industries. Nephrotoxicity is a major adverse effect of chromium poisoning. The present study investigated the potential renoprotective effect of lactoferrin (Lf) against potassium dichromate (PDC)-induced acute kidney injury (AKI) in rats. Beside, because previous studies suggest that interlukin-18 (IL-18) and insulin-like growth factor-1 (IGF-1) play important roles in promoting kidney damage, the present work aimed to evaluate the involvement of these two cytokines in PDC model of AKI and in the potential renoprotective effect of lactoferrin. Adult male albino Wistar rats were pretreated with Lf (200mg/kg/day, p.o.) or (300mg/kg/day, p.o.); the doses that are usually used in the experiment studies, for 14 days followed by a single dose of PDC (15mg/kg, s.c.). PDC caused significant increase in serum urea, creatinine, and total protein levels. This was accompanied with decreased renal glutathione content, and increased renal malondialdehyde, IL-18, IL-4, nuclear factor kappa B (NFκB), IGF-1, and the phosphorylated form of forkhead box protein O1 (FoxO1) levels. Moreover, normal expression IFN-γ mRNA and enhanced expression of TNF-α mRNA was demonstrated in renal tissues. Histopathological investigations provoked deleterious changes in the renal tissues. Tubular epithelial hyperplasia and apoptosis were demonstrated immunohistochemically by positive proliferating cell nuclear antigen (PCNA), Bax, and Caspase-3 expression, respectively. Pretreatment of rats with Lf in both doses significantly corrected all previously mentioned PDC-induced changes with no significant difference between both doses. In conclusion, the findings of the present study demonstrated the involvement of oxidative stress, inflammatory reactions, tubular hyperplasia and apoptosis in PDC-induced AKI. It suggested a role of IL-18 through stimulation of IL-4-induced inflammatory pathway, and IGF-1 through triggering FoxO1-induced cell proliferation. Moreover, the study revealed that Lf protected the kidney against Cr-induced AKI in rats and significantly showed antioxidant, anti-inflammatory, and anti-proliferative properties with down-regulation of IL-18 and IGF-1.

Radon inhalation suppresses nephropathy in streptozotocin-induced type-1 diabetic mice

In this study, we investigated the suppressive effects of radon inhalation against nephropathy in C57BL/6J mice with type-1 diabetes induced by intraperitoneal injection of streptozotocin (50 mg/kg weight, given five times). Four weeks after diabetes induction, the diabetic mice were continuously treated with inhaled radon-222 of 2000 Bq/m3 or air only (sham) for four weeks. The results showed that radon inhalation did not affect type-1 diabetic symptoms such as body weight loss, hyperglycemia, and hypoinsulinemia. However, diabetic mice treated with radon showed lower urinary albumin excretion and fibrotic change in renal glomeruli compared with diabetic mice not treated with radon. Furthermore, renal superoxide dismutase activity and glutathione content were significantly higher in diabetic mice treated with radon than in diabetic mice not treated with radon. These findings suggested that radon inhalation enhanced renal antioxidants activities, resulting in the suppression of diabetic nephropathy. This study may contribute to the development of a novel approach in the treatment of nephropathy for diabetic patients.

Crocin Abrogates Carbon Tetrachloride-Induced Renal Toxicity in Rats via Modulation of Metabolizing Enzymes and Diminution of Oxidative Stress, Apoptosis, and Inflammatory Cytokines.

This work aimed at investigating the potential modulatory effects and mechanisms of crocin against CCl4 -induced nephrotoxicity. Forty male rats were allocated for three weeks treatment with corn oil, CCl4 , crocin, or crocin plus CCl4 . Crocin effectively mitigated CCl4 -induced kidney injury as evidenced by amelioration of alterations in kidney histopathology, renal weight/100 g body weight ratio and kidney functions. Crocin modulated CCl4 -induced disturbance of kidney cytochrom-P450 subfamily 2E1 and glutathione-S-transferase. The attenuation of crocin to kidney injury was also associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of renal glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. Crocin mitigated CCl4 -induced elevation of the renal levels of tumor necrosis factor-alpha, interleukin-6, prostaglandin E2, and active caspases-3. Collectively, crocin alleviated CCl4 -induced renal damage via modulation of kidney metabolizing enzymes, suppression of oxidative stress, inhibition of inflammatory cytokines, PGE2, and active caspase3 in kidney.

Ruta graveolens and its active constituent rutin protect against diethylnitrosamine-induced nephrotoxicity through modulation of oxidative stress

Antioxidant and anti-proliferative activities of Sabah Ruellia tuberosa Bo Eng Cheong, Mohd. Zulkarnain Waslim, Fui Fui Lem, Peik Lin Teoh

Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury.

BackgroundAcetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects.MethodsNinety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal.ResultsAPAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues.ConclusionsWe report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress accompanying APAP over-dose, with subsequent clinically beneficial effects on liver and kidney tissues.

Antinephrotoxic efficacy of Operculina turpethum and its isolated Stigma-5,22dien-3-O-b-D-glucopyranoside against N-Nitrosodimethylamine induced renal carcinogenesis in male mice

Objectives: Human exposure to nitrosamines can result from the formation of N ? nitroso compounds either in food during storage or preparation or in vivo , usually in the stomach. N-Nitrosodimethylamine (NDMA) is one of the main N-nitroso compounds which is commonly found in drinking water and is a potent carcinogen. The therapeutic effect of ethanolic root extract of Operculina turpethum was studied for its possible anti-cancerous potential induced by N- Nitrosodimethylamine in male albino mice as the in vivo model for the study. Methods: Renal malondialdehyde (MDA), Superoxide dismutase (SOD), catalase (CAT), glutathione content (GSH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), protein, cholesterol, urea and creatinine content were measured as oxidant/antioxidant markers. Electron Microscopy investigations of the renal tissue were also performed. One-way ANOVA test was used for comparisons of parameters in study groups. Results: Renal antioxidant defense systems, such as superoxide dismutase, catalase, glutathione peroxidase activities and reduced glutathione level, depleted by NDMA were restored to normal by the treatment. Oral administration of Operculina turpethum ethanolic extract, both crude and isolated groups recovered the enzyme activities and caused significant increase in serum protein, the treatment significantly reduced the elevated serum creatinine and urea levels (p>0.05), (p<0.01), (p<0.001). The ultrastructural electron microscopical analysis showed a decrease in cellular degradation comparing to the intoxicated mice. Conclusion: These findings prove the potential of Operculina turpethum as an antioxidant therapy to counteract mitochondrial and post-mitochondrial oxidative stress generated in kidney upon NDMA treatment thereby acting against renal toxicity by a carcinogen.

Potential Chemoprevention of 7,12-Dimethylbenz[a]anthracene Induced Renal Carcinogenesis by Moringa oleifera Pods and Its Isolated Saponin.

Present investigation shows that hydroethanolic extract of Moringa oleifera (MOHE) and its isolated saponin (SM) attenuates DMBA induced renal carcinogenesis in mice. Isolation of SM was achieved by TLC and HPLC and characterization was done using IR and (1)H NMR. Animals were pre-treated with MOHE (200 and 400mg/kg body weight; p.o), BHA as a standard (0.5 and 1%) and SM (50mg/kg body weight) for 21days prior to the administration of single dose of DMBA (15mg/kg body weight). Administration of DMBA significantly (p<0.001) enhanced level of xenobiotic enzymes. It enhanced renal malondialdehyde, with reduction in renal glutathione content, antioxidant enzymes and glutathione-S-transferase. The status of renal aspartate transaminase, alanine transaminase, alkaline phosphatase and total protein content were also found to be decreased along with increase in total cholesterol in DMBA administered mice. Pretreatment with MOHE and SM significantly reversed the DMBA induced alterations in the tissue and effectively suppressed renal oxidative stress and toxicity.

Pluchea lanceolata protects against Benzo(a) pyrene induced renal toxicity and loss of DNA integrity.

Evidence from epidemiological, experimental and clinical trial data indicates that a plant based diet can reduce the risk of chronic diseases and reduces toxic effects. In the present study, we report the antioxidant and anticlastogenic activity of Pluchea lanceolata (PL), an important medicinal plant, in both in vitro and in vivo model. Benzo(a)pyrene (B(a)P) administration leads to depletion of renal glutathione and its metabolizing enzymes. Pretreatment with PL (100 and 200 mg /kg b.wt) restored renal glutathione content and its dependent enzymes significantly (p<0.001) with simultaneous increase in catalase(CAT), quinone reductase(QR) in mouse kidney. Prophylactic administration of PL prior to B (a) P administration significantly decreased the malondialdehyde(MDA), H2O2 and xanthineoxidase (XO) levels at a significance of p<0.001, at both the doses. PL extract pretreated groups showed marked inhibition in B(a)P induced micronuclei formation in mouse bone marrow cells with simultaneous restoration of DNA integrity, viz. alkaline unwinding assay and DNA damage shown by gel-electrophoresis. HPTLC confirms the presence of quercetin in plant extract which could be responsible for PL protecting efficacy. In conclusion, the present findings strongly support the antioxidant efficacy of PL, possibly by modulation of antioxidant armory.

Proanthocyanidin and its emerging anti-neoplastic effects: recent insights

To the Editor: Hassan et al. have provided interesting data in their recent article (Hassan et al. 2012). Proanthocyanidins exert significant anti-neoplastic effects in many systemic malignancies. Proanthocyanidins markedly reduce the metastatic ability of prostate malignancies. It also augments intratumoral apoptosis while at the same time inhibiting tumor cell proliferation. Proanthocyanidin administration results in downregulation of androgen receptor expression (Uchino et al. 2010). It also mediates this effect by attenuating the activity of the urokinase plasminogen activator (Neuwirt et al. 2008). It also decreases the DNA-binding activity of NFkappa B. Oligomeric proanthocyanidin complexes are also highly effective in inhibiting prostate cancer growth. They improve the Bax/Bcl-2 ratio within the tumor. It also accentuates p27 activity at the same time. Phosphorylated p42 levels are also increased secondary to proanthocyanidin exposure. Similar effects are seen in colorectal malignancies. It mediates this role by attenuating phosphorylation of PKB Ser (473). It also enhances caspase-3 activity within the tumor (Engelbrecht et al. 2007). At the same time, it decreases PI3-kinase activity. It especially decreases the formation of ‘‘aberrant crypt foci’’ (Nomoto et al. 2004). As a result, apoptosis is markedly augmented within the tumors. Similar effects are seen in pancreatic malignancies. It mediates this role by increasing Bax levels while at the same time decreasing Bcl-2 levels (Prasad et al. 2012). PI3K levels are attenuated at the same time. Akt phosphorylation is also mitigated. Overall all these changes result in increased apoptosis within the pancreatic tumors. Proanthocyanidins are also of clinical benefit in mitigating the side effects of other chemotherapeutic agents. For instance, they reduce cisplatin induced nephrotoxicity. They mediate this protective effect by increasing superoxide dismutase activity (Sayed 2009). Renal glutathione content is also increased secondary to proanthocyanidin administration. It is obvious from the above examples that proanthocyanidins have significant anti-neoplastic effects. Further studies are needed to fully harness these anti-proliferative effects of proanthocyanidins.

The antifibrotic drug halofuginone reduces ischemia/reperfusion-induced oxidative renal damage in rats

AimThe objective of the present study was to evaluate the protective effects of halofuginone against renal ischemia/reperfusion (I/R) injury. Materials and methodsMale Wistar albino rats were unilaterally nephrectomized and the left renal pedicles were occluded for 45 min to induce ischemia and then reperfused for 6 h (early) or for 72 h (late). The rats were treated intraperitoneally with either halofuginone (100 μg/kg/day) or saline 30 min prior to ischemia and the dose was repeated in the late reperfusion groups. In the sham groups, rats underwent unilateral nephrectomy and were treated at similar time points. The animals were decapitated at either 6 h or 72 h of reperfusion and trunk blood and kidney samples were obtained. ResultsI/R injury increased renal malondialdehyde levels, myeloperoxidase activity and reactive oxygen radical levels, and decreased the renal glutathione content. Halofuginone treatment was found to reduce oxidative I/R injury and improve renal function in the rat kidney, as evidenced by reduced generation of reactive oxygen species, depressed lipid peroxidation and myeloperoxidase activity, and increased glutathione levels. ConclusionsThe present findings demonstrate the anti-inflammatory and antioxidant effects of halofuginone in renal I/R injury, supporting its potential use where renal I/R injury is inevitable.

Preventive Effect of GGsTop, a Novel and Selective γ-Glutamyl Transpeptidase Inhibitor, on Ischemia/Reperfusion-Induced Renal Injury in Rats

GGsTop [2-amino-4-{[3-(carboxymethyl)phenyl](methyl)phosphono}butanoic acid], is a novel, highly selective, and irreversible γ-glutamyl transpeptidase (GGT) inhibitor with no inhibitory activity on glutamine amidotransferases. In this study, we investigated the effects of treatment with GGsTop on ischemia/reperfusion-induced renal injury in uninephrectomized rats. Ischemic acute kidney injury (AKI) was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion 2 weeks after contralateral nephrectomy. Renal function in vehicle-treated AKI rats markedly decreased at 1 day after reperfusion. Treatment with GGsTop (1 and 10 mg/kg i.v.) 5 min before ischemia attenuated the ischemia/reperfusion-induced renal dysfunction in a dose-dependent manner. Histopathological examination of the kidney of AKI rats revealed severe renal damage, which was significantly suppressed by the GGsTop treatment. In renal tissues exposed to ischemia/reperfusion, GGT activity was markedly increased immediately after reperfusion, whereas renal superoxide production and malondialdehyde level were significantly increased 6 h after reperfusion. These alterations were abolished by the treatment with GGsTop. In addition, renal glutathione content was decreased by the 45-min ischemia, but its level was markedly elevated by the GGsTop treatment. Our results demonstrate that the novel and highly selective GGT inhibitor GGsTop prevents ischemia/reperfusion-induced AKI. The renoprotective effect of GGsTop seems to be attributed to the suppression of oxidative stress by inhibiting GGT activation, thereby preventing the degradation of glutathione.

CHEMOMODULATORY EFFECT OFNIGELLA SATIVAAND GREEN TEA AGAINST FE-NTA-MEDIATED RENAL OXIDATIVE DAMAGE IN RAT

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent. The present study was designed to underline the protective mechanism of Nigella sativa (NS) and green tea (GT) against Fe-NTA-induced renal damage. Fe-NTA (5 mg Fe/kg body weight, i.p.) enhanced serum urea and creatinine levels, lactate dehydrogenase and N-acetyl-β-D-glucosaminidase activities. A depletion of renal glutathione content concomitant with a reduction in the activities of antioxidant and phase II metabolizing enzymes was detected. Lipid peroxidation, γ-glutamyl transpeptidase, adenosine deaminase and xanthine oxidase activities in renal tissue were markedly increased after Fe-NTA challenge. A significant deposition of iron in kidney and induction of serum prostaglandin E2 level were associated with the enhanced oxidative damage. Pretreatment of rats with either NS oil (2 mL/kg) or GT extract (100 mg/kg) by gavage for 7 consecutive days ameliorated most of the biochemical and histopathological changes induced by Fe-NTA. In conclusion, NS and GT can serve as potent chemopreventive agents to suppress oxidant-induced tissue injury and DNA damage. PRACTICAL APPLICATION Various therapeutic effects, such as anti-inflammatory, anticancer, antidiabetic and antimicrobial effects have been described for Nigella sativa and green tea. The present study is an endeavor in the direction of determining their possible mechanism of protection in Fe-NTA-mediated renal oxidative damage in rats. Our study proved that they both exhibit a renoprotective potential and, hence. they can be used as value-added agents for managing renal diseases as well as conditions associated with oxidative overload.

Attenuation of oxidative stress, inflammation and early markers of tumor promotion by caffeic acid in Fe-NTA exposed kidneys of Wistar rats

Iron nitrilotriacetate (Fe-NTA), a chief environmental pollutant, is known for its extensive toxic manifestations on renal system. In the present study, caffeic acid, one of the most frequently occurring phenolic acids in fruits, grains, and dietary supplements was evaluated for its shielding effect against the Fe-NTA-induced oxidative, inflammatory, and pathological damage in kidney. Fe-NTA was administered (9 mg Fe/kg body weight) intraperitoneally to the Wistar male rats on 20th day while caffeic acid was administered orally (20 and 40 mg/kg body weight) before administration of Fe-NTA. The intraperitoneal administration of Fe-NTA-enhanced lipid peroxidation, xanthine oxidase, and hydrogen peroxide generation with reduction in renal glutathione content, antioxidant enzymes, viz., catalase, glutathione peroxidase, and glutathione reductase. A sharp elevation in the levels of myloperoxidase, blood urea nitrogen (BUN), and serum creatinine has also been observed. Tumor promotion markers viz., ornithine decarboxylase (ODC) and [(3)H] thymidine incorporation into renal DNA were also significantly increased. Treatment of rats orally with caffeic acid (20 and 40 mg/kg body weight) resulted in a significant decrease in xanthine oxidase (P < 0.001), lipid peroxidation (P < 0.001), γ-glutamyl transpeptidase (P < 0.01), and H(2)O(2) (P < 0.01). There was significant recovery of renal glutathione content (P < 0.001) and antioxidant enzymes (P < 0.001). There was also a reversal in the enhancement of renal ODC activity, DNA synthesis, BUN, and serum creatinine (P < 0.001). All these changes were supported by histological observations. The results indicate that caffeic acid may be beneficial in ameliorating the Fe-NTA-induced oxidative damage and tumor promotion in the kidney of rats.

Hyperoxia-Induced Protection against Rat's Renal Ischemic Damage: Relation to Oxygen Exposure Time

Background. Pre-exposure to hyperoxic gas (≥ 95%) has been shown to protect the heart and central nervous system from ischemia-reperfusion injury. In the present study, we investigated whether oxygen pretreatment induces delayed renal protection in rats. The possible role of some renal antioxidant agents was also investigated. Materials and methods. Adult male Wistar rats were kept in a hyperoxic (HO) (≥ 95% O2) environment for 0.5 h, 1 h, 2 h, 3 h, 6 h, and 2 h/day for three consecutive days and 4 h/day for six consecutive days, and control group (IR) animals were kept in the cage with no HO, one day before subjecting their kidney to 40 minutes of ischemia and 24h of reperfusion. Renal function was assessed by comparing plasma creatinine (Cr), blood urea nitrogen (BUN), creatinine clearance (CLCr), and fractional excretion of sodium (FENa%). Histopathological injury score was also determined according to the Jablonski method. To examine the antioxidant system induction by hyperoxia, we measured renal catalase and superoxide dismutase activity, and renal glutathione and malondialdehyde content. Results. Our data demonstrated that only in 4 h/day HO for six consecutive days, the renal function tests (Cr, CLCr, BUN, and FENa%) and Jablonski histological injury were better than control group (p < 0.05). The beneficial effect of oxygen pretreatment in this group was associated with increased renal catalase activity compared with those obtained from control group (p < 0.05). Conclusion. The present study demonstrates that repeated exposure to hyperoxic (≥ 95% O2) environment can reduce subsequent rat's renal ischemia-reperfusion damage. Induction of endogenous antioxidant system may partially explain this beneficial effect of hyperoxic preconditioning.

Effect of Glutathione Depletion on Ifosfamide Nephrotoxicity in Rats

Kidney injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. Previous studies have shown that treatment with ifosfamide reduces kidney glutathione and that the toxicity of ifosfamide is enhanced in glutathione-depleted renal tubule cells in vitro. In this study, we examined the effect of glutathione depletion on ifosfamide nephrotoxicity in vivo using rats treated with the glutathione-depleting agent buthionine sulfoximine. Animals received 80 mg/kg ifosfamide intraperitoneally daily for three days with or without buthionine sulfoximine in drinking water. Buthionine sulfoximine produced a significant fall in renal glutathione content but did not affect kidney function. Ifosfamide-treated rats developedlow-grade glucosuria, phosphaturia and proteinuria that worsened with concomitant buthionine sulfoximine therapy. These findings indicate that glutathione depletion exacerbates ifosfamide nephrotoxicity in rats and suggest that pharmacological methods for replenishing intracellular glutathione may be effective in ameliorating ifosfamide-induced renal injury.