Renal Oxidative Damage Research Articles

A Possible Role of Nrf2 in Prevention of Renal Oxidative Damage by Ferric Nitrilotriacetate

To ascertain the possible roles of nuclear erythroid 2 p45-related factor 2 (Nrf2), a key transcription factor of phase 2 drug-metabolizing enzymes, in renal cellular defense against oxidative stress, wild-type and Nrf2-knockout -/- mice were treated with ferric nitrilotriacetate (Fe-NTA) at doses of 3 or 6 mg iron/kg body weight. After Fe-NTA treatment, Nrf2 -/- mice consistently showed lower levels of glutathione (GSH) in the kidney at the low dose and the liver at the high dose than the wild-type mice. Gamma-glutamylcysteine ligase (GCL) activity in the kidney and liver of Nrf2-/- mice was also consistently lower than in wild-type mice after the Fe-NTA treatment. Histopathological examination revealed that nephrotoxicity of Fe-NTA, reflected in necrosis of renal tubule epithelial cells following nuclear damage, was more severe in the Nrf2-/- mice than in their wild-type counterparts. Overall, the data suggest that Nrf2 -/- mice are unable to compensate for depletion of renal GSH because of oxidative stress, being more susceptible to Fe-NTA-induced nephrotoxicity. In conclusion, the present study showed that Nrf2 might play an important role in protecting cells from oxidative stress in the kidney through its regulation of antioxidant enzymes.

Protective effects of cranberries on infection-induced oxidative renal damage in a rabbit model of vesico-ureteric reflux

OBJECTIVE To evaluate the protective effects of cranberry fruit, which have known antioxidant effects, on infection-induced oxidative renal damage in a rabbit model of vesico-ureteric reflux (VUR). MATERIALS AND METHODS In all, 36 New Zealand male rabbits were divided into five groups, with a sham operation in four rabbits serving as the control (group 1). To create unilateral VUR the roof of the left intravesical ureter was incised, and VUR confirmed 2 weeks after surgery. In all, 32 rabbits with VUR were divided into four groups; 2, VUR alone (with sterile urine); 3, a group infected with Escherichia coli; 4, with intravesical E. coli instillation but fed cranberries; and 5, intravesical E. coli instillation plus an intraperitoneal injection with melatonin group. At 3 weeks after surgery the rabbits were killed, the kidneys obtained and examined histopathologically to evaluate inflammation, fibrosis and tubular changes. Oxidative renal damage was evaluated by measuring malondialdehyde in the renal tissue. RESULTS Grossly, the refluxing kidney was larger than the contralateral normal kidney, and the refluxing ureter was dilated and tortuous. Microscopy of tissues from the kidneys in group 3 showed apparent periglomerular mononuclear cell infiltration, tubular dilatation and atrophy, and interstitial fibrosis. The kidneys from groups 2, 4 and 5 showed mild mononuclear cell infiltration with no interstitial fibrosis. The level of malondialdehyde in the kidneys of group 3 was significantly higher than that in group 2, 4 and 5 (P < 0.05); the level in groups 4 and 5 did not differ significantly from that in group 2. CONCLUSIONS This study shows that cranberries have an anti-inflammatory effect through their antioxidant function and might prevent infection-induced oxidative renal damage. Thus, clinically cranberries might be used as a beneficial adjuvant treatment to prevent damage due to pyelonephritis in children with VUR.

Chronic Oxidative Stress Causes Amplification and Overexpression of ptprz1 Protein Tyrosine Phosphatase to Activate β-Catenin Pathway

Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase zeta or receptor tyrosine phosphatase beta) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16 approximately 552-fold in the RCCs. Network analysis of the expression revealed the involvement of the beta-catenin pathway in the RCCs. In the RCCs, dephosphorylated beta-catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear beta-catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating beta-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification.

Protective effect of melatonin against formaldehyde-induced kidney damage in rats

This study was undertaken to investigate the protective effects of melatonin against formaldehyde-induced renal damage in rats. For this purpose, 21 male Wistar rats were divided into three groups. The animals in Group I were used as a control, whereas the rats in group II were injected every other day with formaldehyde. The rats in group III received melatonin daily while exposed to formaldehyde. At the end of the 14-day experimental period, all rats were killed by decapitation, and the kidneys were removed. Some of the renal tissue specimens were used for determination of superoxide dismutase, glutatione peroxidase enzyme activities, and malondialdehyde levels. The remaining kidney tissue specimens were used for light microscopic evaluation. The renal tissue activities of superoxide dismutase and glutatione peroxidase were significantly decreased, and malondialdehyde levels were significantly increased in rats treated with formaldehyde compared with those of the control animals. In the light microscopic evaluation of this group, degenerative glomerules, vacuolization and dilatation of distal tubules, and vascular congestion were detected. However, an increase was observed in activities of superoxide dismutase and glutatione peroxidase enzymes, and a decrease of malondialdehyde levels in animals treated with formaldehyde plus melatonin was observed. Furthermore, the histopathological changes caused by formaldehyde were disappeared except for minimal tubular dilatation in this group. In conclusion, the biochemical and histological findings of our study suggest that melatonin administration prevents formaldehyde-induced oxidative renal damage in rats.

The Protective Effect of Curcumin Against Gentamicin-Induced Renal Dysfunction and Oxidative Stress in Male Albino Rats

Background: Generation of free radicals in the renal cortex plays an important role in the pathogenesis of gentamicin-induced nephrotoxicity. Curcumin, the yellow curry pigment isolated from turmeric, has been confirmed to have a strong antioxidant and free radical scavenging actions. In the present study, we investigated the possible protective effect of curcumin against gentamicin-induced nephropathy in male albino rats. Methods: Thirty two male albino rats were divided into 4 equal groups (Gr.): (Gr.I) control, injected i.p with 1cc isotonic saline solution/day for 8 wks; (Gr.II) received 200 mg/kg/day curcumin (Cur. ) orally, suspended in normal saline, for 8 wks ; (Gr.III) injected I.p by 100 mg/kg/day gentamicin (Gen.) for 8 days followed by 1cc saline I.p thereafter; (Gr.IV) (Cur./Gen.) received 200 mg/kg/day Cur. for one week before starting Gen injection (100 mg/kg/day) for 8 days during which Cur. was received concurrently with Gen then Cur administration was continued thereafter throughout the rest of the study (6 wks). Body weight was recorded weekly. Renal function was evaluated by measuring the 24 h. urine output, the concentrations of plasma creatinine, blood urea nitrogen (BUN) and creatinine clearance. Also, kidney weight and the parameters of oxidative stress: reduced glutathione (GSH), thiobarbituric acid reacting substance (TBARS) and the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) were measured in kidney tissue. Results: The Kidney weight, plasma creatinine, BUN and 24 h urine output were significantly increased while the body weight and creatinine clearance were significantly decreased (P < 0.0005), in rats treated with Gen. as compared to control. While Cur. could significantly normalize the previous parameters. In addition Gen. caused oxidative stress in kidney as seen by significant increase in TBARS level, and significant decrease of catalase, GSH, SOD and GPX activities (P < 0.0005), However, Cur. could normalize all the above parameters as compared to control. Conclusion: Our data indicate that Cur. could suppress renal toxicity by blocking oxidative injury in the kidney and restore the antioxidant enzymatic profile. The renoprotective effect of Cur. is also evident by a remarkable improvement of renal function in Gen. injected rats. So Cur. can be used as a potent protective agent against renal oxidative damage mediated by Gen.

The Protective Effect of Curcumin Against Gentamicin-Induced Renal Dysfunction and Oxidative Stress in Male Albino Rats

Background: Generation of free radicals in the renal cortex plays an important role in the pathogenesis of gentamicin-induced nephrotoxicity. Curcumin, the yellow curry pigment isolated from turmeric, has been confirmed to have a strong antioxidant and free radical scavenging actions. In the present study, we investigated the possible protective effect of curcumin against gentamicin-induced nephropathy in male albino rats. Methods: Thirty two male albino rats were divided into 4 equal groups (Gr.): (Gr.I) control, injected i.p with 1cc isotonic saline solution/day for 8 wks; (Gr.II) received 200 mg/kg/day curcumin (Cur. ) orally, suspended in normal saline, for 8 wks ; (Gr.III) injected I.p by 100 mg/kg/day gentamicin (Gen.) for 8 days followed by 1cc saline I.p thereafter; (Gr.IV) (Cur./Gen.) received 200 mg/kg/day Cur. for one week before starting Gen injection (100 mg/kg/day) for 8 days during which Cur. was received concurrently with Gen then Cur administration was continued thereafter throughout the rest of the study (6 wks). Body weight was recorded weekly. Renal function was evaluated by measuring the 24 h. urine output, the concentrations of plasma creatinine, blood urea nitrogen (BUN) and creatinine clearance. Also, kidney weight and the parameters of oxidative stress: reduced glutathione (GSH), thiobarbituric acid reacting substance (TBARS) and the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPX) were measured in kidney tissue. Results: The Kidney weight, plasma creatinine, BUN and 24 h urine output were significantly increased while the body weight and creatinine clearance were significantly decreased (P < 0.0005), in rats treated with Gen. as compared to control. While Cur. could significantly normalize the previous parameters. In addition Gen. caused oxidative stress in kidney as seen by significant increase in TBARS level, and significant decrease of catalase, GSH, SOD and GPX activities (P < 0.0005), However, Cur. could normalize all the above parameters as compared to control. Conclusion: Our data indicate that Cur. could suppress renal toxicity by blocking oxidative injury in the kidney and restore the antioxidant enzymatic profile. The renoprotective effect of Cur. is also evident by a remarkable improvement of renal function in Gen. injected rats. So Cur. can be used as a potent protective agent against renal oxidative damage mediated by Gen.

Renoprotective effect of Erdosteine in rats against gentamicin nephrotoxicity: a comparison of 99mTc-DMSA uptake with biochemical studies

Erdosteine is a mucolytic agent having antioxidant properties through its active metabolites in acute injuries induced by pharmacological drugs. This study was designed to investigate the renoprotective potential of Erdosteine against gentamicin (GM)-induced renal dysfunction by using Technetium-99 m dimercaptosuccinic acid (Tc-99 m DMSA) uptake and scintigraphy in rats. For this purpose, male Wistar rats were randomly allotted into one of the four experimental groups: Control, Erdosteine, GM, and GM + Erdosteine groups. GM and GM + Erdosteine groups received 100 mg/kg GM intramuscularly for 6 days. In addition, Erdosteine and GM + Erdosteine groups received 50 mg/kg Erdosteine orally for 6 days. Renal function tests were assessed by serum blood urea nitrogen (BUN), creatinine levels, as well as scintigraphic and tissue radioactivity measurements with Tc-99 m DMSA. Renal oxidative damage was determined by renal malondialdehyde (MDA) levels, by antioxidant enzyme activities; superoxide dismutase (SOD) and catalase (CAT) and activities of oxidant enzymes; xanthine oxidase (XO) and myeloperoxidase (MPO). GM administration resulted in marked renal lipid peroxidation, increased XO and MPO activities and decreased antioxidant enzyme activities. GM + Erdosteine group significantly had lower MDA levels, higher SOD and CAT activities and lower XO and MPO activities, when compared to GM. Also GM + Erdosteine had lower levels of serum BUN, creatinine and higher renal tissue Tc-99 m DMSA uptake and radioactivity with respect to GM. In conclusion, our results supported a protective role of Erdosteine in nephrotoxicity associated with GM treatment.

Protective effects of cranberries on infection‐induced oxidative renal damage in a rabbit model of vesico‐ureteric reflux

To evaluate the protective effects of cranberry fruit, which have known antioxidant effects, on infection-induced oxidative renal damage in a rabbit model of vesico-ureteric reflux (VUR). In all, 36 New Zealand male rabbits were divided into five groups, with a sham operation in four rabbits serving as the control (group 1). To create unilateral VUR the roof of the left intravesical ureter was incised, and VUR confirmed 2 weeks after surgery. In all, 32 rabbits with VUR were divided into four groups; 2, VUR alone (with sterile urine); 3, a group infected with Escherichia coli; 4, with intravesical E. coli instillation but fed cranberries; and 5, intravesical E. coli instillation plus an intraperitoneal injection with melatonin group. At 3 weeks after surgery the rabbits were killed, the kidneys obtained and examined histopathologically to evaluate inflammation, fibrosis and tubular changes. Oxidative renal damage was evaluated by measuring malondialdehyde in the renal tissue. Grossly, the refluxing kidney was larger than the contralateral normal kidney, and the refluxing ureter was dilated and tortuous. Microscopy of tissues from the kidneys in group 3 showed apparent periglomerular mononuclear cell infiltration, tubular dilatation and atrophy, and interstitial fibrosis. The kidneys from groups 2, 4 and 5 showed mild mononuclear cell infiltration with no interstitial fibrosis. The level of malondialdehyde in the kidneys of group 3 was significantly higher than that in group 2, 4 and 5 (P < 0.05); the level in groups 4 and 5 did not differ significantly from that in group 2. This study shows that cranberries have an anti-inflammatory effect through their antioxidant function and might prevent infection-induced oxidative renal damage. Thus, clinically cranberries might be used as a beneficial adjuvant treatment to prevent damage due to pyelonephritis in children with VUR.

The effects of methylene blue on renal scarring due to pyelonephritis in rats

The aim of this study was to evaluate the efficiency of methylene blue (MB) in preventing renal scar formation after the induction of pyelonephritis (PNP) in a rat model with delayed antimicrobial therapy. An inoculum of the K-12 strain of Escherichia coli was injected into both kidneys. Control groups received isotonic saline instead of bacterial solution. Four equal groups were then formed: the PNP group was untreated and the PNP ciprofloxacin (CIP) treated group was treated only with CIP intraperitoneally (i.p.) starting on the third day following bacterial inoculation. In the PNP (MB)-treated group, MB was given i.p., and in the PNP MB + CIP-treated group, MB + CIP were administered i.p.. In the sixth week following bacterial inoculation, all rats were sacrificed, and both kidneys of the rats in all groups were examined biochemically and histopathologically for renal scarring. Renal scar was significant in the groups treated with MB alone or MB + CIP combination compared with untreated or antibiotic only groups. Delayed treatment with antibiotics had no effect on scarring. These results suggest that the addition of MB to the delayed antibiotic therapy might be beneficial in preventing PNP-induced oxidative renal tissue damage.

Protective effects of cranberry on infection-induced oxidative renal damage in vesicoureteral reflux in a rabbit model

Purpose We evaluated the protective effects of cranberry, which is known as a fruit with anti-oxidative function, on infection-induced oxidative renal damage in rabbits with experimental VUR. Material and methods A total of 36 New Zealand male rabbits were divided into 5 groups. VUR was created by incising the roof of the left intravesical ureter and confirmed 2 weeks after operation. Infection was induced by intravesical instillation of 2 ml of E. coli suspension (105 E. coli in 1 ml). Cranberry powder (1 g/kg/day) was supplied with feed during the experimental period. Melatonin was injected into the peritoneal cavity immediately after operation and every week. 3 weeks after operation the rabbits were sacrificed and the kidneys obtained. Oxidative renal damage was evaluated by measuring malondialdehyde in the renal tissue. Group procedure control (n=4) Shamp operation sterile (n=8) VUR + sterile urine E.coli (n=8) VUR + infected urine cranberry (n=8) VUR + infected urine + cranberry melatonin (n=8) VUR + infected urine + melatonin Results The kidneys from E. coli group showed apparent periglomerular mononuclear cell infiltration, tubular dilatation and atrophy, and interstitial fibrosis. The kidneys from the reflux, cranberry and melatonin group showed mild mononuclear cell infiltration without interstitial fibrosis. The level of malondialdehyde in the E. coli group was significantly higher than that in the control, cranberry and melatonin group (p group Mean MDA ± SD (μM/gm) control 3.01±1.41 sterile 3.97±1.52 E. coli 5.12±1.54∗ cranberry 3.47±1.34 melatonin 2.69±0.97 Conclusions This study demonstrates that cranberry has an anti-inflammatory effect by anti-oxidative function and may prevent infection-induced oxidative renal damage. Thus clinically cranberry may be used for a beneficial adjuvant treatment to prevent renal damage due to pyelonephritis in children with VUR.

Protective Effects of Cranberry on Infection-induced Oxidative Renal Damage in a Vesicoureteral Reflux Rabbit Model

Purpose: We evaluated the protective effects of cranberry, which is known as a fruit with anti-oxidative effects, on infection-induced oxidative renal damage with using a rabbit vesico-ureteral reflux (VUR) model. Materials and Methods: New Zealand male rabbits were divided into 5 groups (the control group, VUR group, E. coli group, cranberry group and melatonin group). VUR was created and confirmed at 2 weeks after the operation. Infection was induced by intravesical instillation of an E. coli suspension. Cranberry powder was supplied with the feed. Melatonin was injected into the peritoneal cavity. The rabbit kidneys were obtained 3 weeks after the operation. Histopathologic examination was performed to evaluate for inflammation, fibrosis and the tubular change. The oxidative renal damage was evaluated by measuring malondialdehyde (MDA) in the renal tissue. Results: Grossly, the refluxing kidney was larger than the contralateral normal kidney and the refluxing ureter was dilated and tortuous. The microscopic observation of the kidneys from the E. coli group showed apparent periglomerular mononuclear cell infiltration, tubular dilatation and atrophy, and interstitial fibrosis. The kidneys from the reflux group, cranberry group and melatonin group showed mild mononuclear cell infiltration without interstitial fibrosis. The MDA level in the kidneys of the E. coli group was significantly higher than that in the control, cranberry and melatonin groups (p<0.05). The MDA level in the cranberry and melatonin groups didn't significantly differ from that in the sterile group. Conclusions: This study demonstrates that cranberry has an anti-inflammatory effect due to an anti-oxidative function and it may prevent infection-induced oxidative renal damage. But application of cranberry in children with VUR needs more clinical studies. (Korean J Urol 2007;48: 536-541)

Oxidative renal damage in pyelonephritic rats is ameliorated by montelukast, a selective leukotriene CysLT1 receptor antagonist

Urinary tract infections may induce severe inflammation, transient impairment in renal function and scar formation, ranging in severity from acute symptomatic pyelonephritis to chronic pyelonephritis, which have a potential to lead to renal failure and death. The present study aimed to investigate the possible protective effect of montelukast, a selective antagonist of cysteinyl leukotriene receptor 1 (leukotriene CysLT1), against Escherichia coli-induced oxidative injury and scarring in renal tissue. Wistar rats were injected 0.1 ml of E. coli (ATCC 25922 10 10 cfu/ml) or saline into left renal medullae. Six rats were assigned as the sham group and were given 0.1 ml 0.9% NaCl. Pyelonephritic rats were treated with either saline or montelukast immediately after surgery and at daily intervals. Twenty-four hours or one week after E. coli injection, rats were decapitated and the kidney samples were taken for histological examination or determination of renal malondialdehyde, glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen contents. Formation of reactive oxygen species in renal tissue samples was monitored by using chemiluminescence technique with luminol and lucigenin probes. Creatinine, blood urea nitrogen and lactate dehydrogenase (LDH) activity were measured in the serum samples. E. coli inoculation caused significant increases in malondialdehyde level, MPO activity, chemiluminescence levels and collagen content, while GSH level was decreased in the renal tissues ( p < 0.05–0.001). On the other hand, serum TNF-alpha, LDH, blood urea nitrogen and serum creatinine levels were elevated in the pyelonephritic rats as compared to control group. Leukotriene CysLT1 receptor antagonist montelukast reversed all these biochemical indices, as well as histopathological alterations, that were induced by acute pyelonephritis. It seems likely that montelukast protects kidney tissue by inhibiting neutrophil infiltration, balancing oxidant–antioxidant status, and regulating the generation of inflammatory mediators suggesting a future role for leukotriene CysLT1 receptor antagonists in the treatment of pyelonephritis.

Protective effect of Didymocarpus pedicellata on ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and hyperproliferative response

Didymocarpus pedicellata R. Br. (Gesneriaceae) is widely used in traditional Indian medicines against renal afflictions. In the present study, we have revealed ethanolic extract of aerial parts of D. pedicellata to possess significant antioxidant activity and protect against ferric nitrilotriacetate (Fe-NTA) mediated renal oxidative stress, nephrotoxicity and tumor promotion response. D. pedicellata extract was found to possess a high content of total polyphenolics, exhibit potent reducing power and significantly scavenge free radicals including several reactive oxygen species (ROS) and reactive nitrogen species (RNS). The extract also significantly and dose-dependently protected against Fe-NTA plus H(2)O(2)-mediated damage to lipids and DNA. Protective efficacy of the extract was also tested in vivo against Fe-NTA mediated nephrotoxicity and tumor promotion response. Administration of Fe-NTA (9 mg/kg body weight, i.p.) to Swiss albino mice depleted renal glutathione content and activities of antioxidant and phase II metabolizing enzymes with concomitant induction of oxidative damage. Fe-NTA also incited hyperproliferation response elevating ornithine decarboxylase activity and [(3)H]-thymidine incorporation into DNA. Elevation in serum creatinine (SCr) and blood urea nitrogen (BUN), and histopathological changes were also evident and suggested Fe-NTA to afflict damage to kidney. Pretreatment of mice with D. pedicellata extract (100-200 mg/kg body weight) for 7 days not only restored antioxidant armory near normal values but also significantly protected against renal oxidative stress and damage restoring normal renal architecture and levels of renal damage markers, viz., BUN and SCr. The results of the present study indicate D. pedicellata to possess potent antioxidant and free radical scavenging activities and preclude oxidative damage and hyperproliferation in renal tissues.

The effects of n-acetylcysteine on methotrexate-induced oxidative renal damage in rats

The effects of n-acetylcysteine on methotrexate-induced oxidative renal damage in rats

Deletion and single nucleotide substitution at G:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces oxidative renal proximal tubular damage that subsequently leads to a high incidence of renal cell carcinoma in rodents, presenting an intriguing model of free radical-induced carcinogenesis. In the present study, we used gpt delta transgenic mice, which allow efficient detection of point mutations and deletions in vivo, to evaluate the mutation spectra, in association with the formation of 8-oxoguanine and acrolein-modified adenine during the first 3 weeks of carcinogenesis. Immunohistochemical analysis revealed the highest levels of 8-oxoguanine and acrolein-modifed adenine in the renal proximal tubules after 1 week of repeated administration. DNA immunoprecipitation and quantitative polymerase chain reaction analysis showed that the relative abundance of 8-oxoguanine and acrolein-modified adenine at the gpt reporter gene were increased at the first week in the kidney. Similarly, in both 6-thioguanine and Spi(-) selections performed on the renal specimens after Fe-NTA administration, the mutant frequencies were increased in the Fe-NTA-treated mice at the first week. Further analyzes of 79 mutant clones and 93 positive plaques showed a high frequency of G:C pairs as preferred targets for point mutation, notably G:C to C:G transversion-type mutation followed by deletion, and of large-size (>1 kilobase) deletions with short homologous sequences in proximity to repeated sequences at the junctions. The results demonstrate that the iron-based Fenton reaction is mutagenic in vivo in the renal tubular cells and induces characteristic mutations.

α-Tocopherol induces calnexin in renal tubular cells: Another protective mechanism against free radical-induced cellular damage

Pre-administration of α-tocopherol is protective against oxidative renal tubular damage and subsequent carcinogenesis by ferric nitrilotriacetate (Fe-NTA) in rats. We searched for mechanisms other than the scavenging effect of α-tocopherol with microarray analyses, which implicated calnexin, a chaperone for glycoproteins. Renal mRNA levels of calnexin significantly increased 3 h after an injection of Fe-NTA in rats fed a standard diet whereas those fed an α-tocopherol-supplemented diet showed an increase prior to injection, but after injection showed a decrease in renal calnexin mRNA levels, with unaltered protein levels. In experiments using LLC-PK1 cells, addition of α-tocopherol was protective against oxidative stress by H 2O 2, concomitant with calnexin induction. Knockdown of calnexin by siRNA significantly reduced this protection. Furthermore, COS-7 cells transfected with the calnexin gene were more resistant to H 2O 2. Together with the fact that α-tocopherol induced N-acetylglucosaminyltransferase 3, our data suggest that α-tocopherol modifies glycoprotein metabolism partially by conferring mild ER stress. This adds another molecular mechanism of α-tocopherol toward cancer prevention.

Ascorbic acid and α-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study

Background Oxidative stress, resulting from an imbalance between prooxidant and antioxidant systems in favor of the former, largely contributes to immune system deregulation and complications observed in end-stage renal disease (ESRD) and patients treated with hemodialysis. Reactive oxygen species and free radicals are involved in the nephrotoxicity induced by a synthetic anticancer drug cisplatin. Methods A comparative study on the nephroprotective effects of antioxidant vitamins (250 and 500 mg/kg, p.o.), vitamin C (ascorbic acid) and vitamin E (α-tocopherol), was evaluated using cisplatin (10 mg/kg body wt, i.p.) induced oxidative renal damage in mice. Urea and creatinine in serum were estimated for the renal function. Antioxidant status was estimated in kidney homogenate. Results We found that both vitamins at 500 mg/kg significantly ( P < 0.01) protected the nephrotoxicity induced by cisplatin. The cisplatin induced increase of urea and creatinine concentrations were reduced in the vitamins plus cisplatin (250 and 500 mg/kg, p.o.)-treated groups. However the cisplatin induced decline of renal antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities were increased only in the 500 mg/kg vitamins treated groups. Both vitamins at 250 and 500 mg/kg could increase the concentration of reduced glutathione (GSH) and protected the increase of cisplatin induced lipid peroxidation. Conclusions Higher doses of vitamins are effective to protect oxidative renal damage and vitamin C is the better nephroprotective agent than vitamin E. The protection is mediated partially by preventing the decline of renal antioxidant status.

Modulatory Effects of Shape Pluchea Lanceolata Against Chemically Induced Oxidative Damage, Hyperproliferation And Two-Stage Renal Carcinogenesis in Wistar Rats

Ferric nitrilotriacetate (Fe-NTA) is a well-established renal carcinogen. Here, we have shown that Pluchea lanceolata (PL) belonging to the family Asteraceae. PL attenuates Fe-NTA induced renal oxidative stress, hyperproliferative response and renal carcinogenesis in rats. It promoted DEN (N-diethyl nitrosamine) initiated renal carcinogenesis by increasing the percentage incidence of tumors and induces early tumor markers viz. ornithine decarboxylase (ODC) and renal DNA synthesis. Fe-NTA (9 mg Fe/kg body weight, intraperitoneally) also enhances renal lipid peroxidation (LPO), xanthine oxidase (XO) and hydrogen peroxide (H(2)O(2)) generation with reduction in renal glutathione content (GSH), antioxidant enzymes, viz., glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), glucose-6-phosphate dehydrogenase and phase-II metabolizing enzymes such as glutathione-S-transferase and quinone reductase (QR). It also enhances blood urea nitrogen (BUN) and serum creatinine. Oral treatment of rats with PL extract (100 and 200 mg/kg body weight) resulted in significant decrease in lipid peroxidation (LPO), xanthine oxidase (XO), H(2)O(2) generation, blood urea nitrogen (BUN), serum creatinine, renal ODC activity, DNA synthesis (p < 0.001) and incidence of tumors. Renal glutathione content (p < 0.01), its metabolizing enzymes (p < 0.001) and antioxidant enzymes were also recovered to significant level (p < 0.001). Thus, present study supports PL as a potent chemopreventive agent and suppresses Fe-NTA-induced renal carcinogenesis and oxidative damage response in Wistar rat.

Curcumin attenuates gentamicin-induced renal oxidative damage in rats

The present investigation reports the effect of curcumin, an antioxidant, on gentamicin-induced-renal oxidative damage in rats. Curcumin (200 mg/kg p.o.) was administered for 2 weeks before and 1 week simultaneously with gentamicin (100 mg/kg i.p.). Saline treated rats served as control. Serum creatinine, blood urea (BUN), urinary protein, glucose, urine gamma glutamyl transferase and urine volume increased in rats treated with gentamicin while creatinine clearance decreased compared to controls P < 0.001. Renal histological examination revealed tubular necrosis. Curcumin significantly normalized the above parameters. Gentamicin decreased the activities of catalase (CAT), gutathione peroxidase (GSHPx) and the level of glutathione (GSH) but the activity of copper, zinc–superoxide dismutase (Cu, Zn–SOD) was unaltered compared to control. Curcumin attenuated the gentamicin-induced reduction in the activities of CAT, GSHPx and level of GSH by 31%, 55% and 74%, respectively. Curcumin attenuated the gentamicin-induced increases in both plasma malondialdehyde (MDA) and kidney MDA by 57% and 62%, respectively, as well as lipid hydroperoxide (LOOH) formation by 52% and 56% in rat plasma and kidney, respectively. However, Curcumin did not reduce gentamicin-induced formation of LOOH, both in the plasma and kidney, in the presence of exogenous oxidants (1 mM FeSO 4, 1 mM ascorbate, 0.2 mM H 2O 2). Our data indicate that the natural antioxidant curcumin can be a potent protective agent against renal oxidative damage mediated by gentamicin.

Mesna Protects Intestinal Mucosa from Ischemia/Reperfusion Injury

Mesna is a thiol used for the prevention of oxazaphosphorine-induced hemorrhagic cystitis. However, its antioxidant properties on renal and hepatorenal oxidative damage, as well as its mucoprotective effect on the intestinal epithelium have also been shown. The aim of this study was to investigate the potential beneficial effect of mesna on ischemia/reperfusion (I/R)-induced oxidant damage of the intestinal mucosa. Wistar rats were subjected to intestinal I/R for 30 min, induced by occlusion of the superior mesenteric artery, followed by 60 min reperfusion. Mesna was administered at 3 time points relative to ischemia; 60 min before ischemia, at the onset of ischemia or at the onset of reperfusion. At the end of the study period, jejunal segments were excised and assessed for histopathologic score, apoptotic index using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) assay and glutathione/glutathione disulfide (GSH/GSSG) ratio, as a marker of oxidative stress. I/R caused deterioration of histological characteristics and induction of apoptosis and oxidative stress in the intestinal mucosa. Changes regarding histology and apoptosis were prevented when mesna was administered 60 min before ischemia, but were attenuated when mesna was administered at the onset of ischemia or reperfusion. In all mesna groups, oxidative stress was reduced. Mesna can ameliorate or even prevent intestinal I/R injury by reducing oxidative stress.