The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats

Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent.     

Effect of Spirulina, a blue green algae, on gentamicin-induced oxidative stress and renal dysfunction in rats

Gentamicin (GM), an aminoglycoside, is widely employed in clinical practice for the treatment of serious Gram-negative infections. The clinical utility of GM is limited by the frequent incidence of acute renal failure. Experimental evidences suggest that oxidative and nitrosative stress play an important role in GM nephrotoxicity. Spirulina fusiformis is a blue green algae with potent free radical scavenging properties. The present study was designed to investigate renoprotective potential of S. fusiformis, against GM-induced oxidative stress and renal dysfunction. Spirulina fusiformis (500, 1000, 1500 mg/kg, p.o.) was administered 2 days before and 8 days concurrently with GM (100 mg/kg, i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen and creatinine clearance and serum nitrite levels. Renal oxidative stress was determined by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of superoxide dismutase (SOD) and catalase. Chronic GM administration resulted in marked renal oxidative and nitrosative stress and significantly deranged renal functions. Treatment with S. fusiformis significantly and dose-dependently restored renal functions, reduced lipid peroxidation and enhanced reduced glutathione levels, SOD and catalase activities. The results of present study clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of S. fusiformis in GM-induced nephrotoxicity.     

Modulation of gentamicin-induced renal dysfunction and injury by the phenolic extract of soybean (Glycine max)

Gentamicin (GM) is one of the most important of the aminoglycoside antibiotics used widely for the treatment of serious and life-threatening infections and whose clinical use is limited by its nephrotoxicity. As the pathogenesis of GM-induced renal dysfunction and injury involves reactive oxygen species, the polyphenolic constituents of soybean with antioxidant property may protect against GM-induced renal toxicity. We therefore tested this hypothesis using phenolic extract of soybean (PESB) on GM-induced nephrotoxicity rat model. Administration of GM (80 mg/kg, s.c.) for 12 days to rats induced marked renal failure, characterized by a significantly increased plasma creatinine, urea and Na(+) ions levels, with K(+) depletion. This was also associated with decreases in the activity of the renal antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST)] measured and depletion of both blood and renal reduced glutathione (GSH) levels. The activities of membrane-bound glucose-6-phosphatase (G6Pase) and 5(1)-nucleotidase (5(1)-NTD) enzymes as well as gamma-glutamyltransferase (gamma-GT) and aspartate aminotransferase (AST) (enzymes that are located in the proximal tubule) were decreased. Renal histology examination further confirmed the damage to the kidney as it reveals severe necrosis of the proximal renal tubules with deposition of colloid casts. These alterations were ameliorated in rats pretreated with PESB. The decrease in the activities of SOD, CAT, GST as well as GSH depletion observed in GM-treated rats was prevented in the rats pretreated with PESB. The activities of gamma-GT, AST and G6Pase were also increased in the kidney. These protective effects were dose dependent except for G6Pase activity and GSH levels that were preserved only at 500 mg/kg dose of PESB, and 5'-NTD activity that was dose dependently decreased. Furthermore, the extent of tubular damage induced by GM was reduced in rats that also received PESB. The lower dose (500 mg/kg) of the extract, however, appeared to provide better histological protection. These results suggest that the PESB has protective effects on GM-mediated nephropathy and this may be related to the action of the antioxidant polyphenolic content of the soybean.     

The protective effect of eugenol against gentamicin-induced nephrotoxicity and oxidative damage in rat kidney

Gentamicin (GM) is an effective aminoglycoside antibiotic against life-threatening Gram-negative bacteria. However, a major complication of therapeutic doses of GM is nephrotoxicity, which is believed to be related to the generation of reactive oxygen species. The present study was therefore aimed to investigate the protective effect of eugenol, a phenolic antioxidant, on GM-induced nephrotoxicity in Sprague-Dawley rats. Intramuscular injection of rats with GM (80 mg/kg body weight/day) for six consecutive days induced marked acute renal failure, manifested by a sharp significant increase in serum urea and creatinine levels, along with a significant depletion of serum potassium level, compared to normal controls. GM-induced renal dysfunction was attributable to enhanced oxidative stress, as revealed by decreased superoxide dismutase and catalase activities, glutathione depletion and increased lipid peroxidation. Furthermore, kidney lactate dehydrogenase activity, as an indicator of hypoxia, was significantly increased by GM administration. Eugenol (100 mg/kg body weight, per os) administered four days before and six days concurrently with GM (80 mg/kg body weight, i.m.) restored normal renal functions and suppressed GM-induced oxidative stress and hypoxia. Light microscopical examination of the renal tissues of GM-treated animals demonstrated severe tubular necrosis at the cortex and increased cellular inflammatory processes. However, these alterations were considerably reduced with eugenol coadministration. In conclusion, eugenol ameliorates GM-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing lipid peroxidation and improving intracellular antioxidant defense.     

Abrogation of cisplatin‐induced nephrotoxicity by emodin in rats

Nephrotoxicity of the anticancer drug cisplatin (CP) involves the generation of reactive oxygen species in renal cortex, and emodin (a rhubarb anthraquinone) has strong antioxidant and anticancer actions. Therefore, we tested here the possible ameliorative effect of emodin on CP nephrotoxicity in rats. Emodin was given orally (10 mg/kg/day for nine consecutive days), and on day 4, some of the treated rats were also injected intraperitoneally with either saline or CP (6 mg/kg). Five days after CP treatment, rats were killed, and blood and urine samples, and kidneys were collected for the assessment of histopathological renal damage and apoptosis, and for biochemical estimation of creatinine and urea concentrations in plasma and urine, several cytosolic antioxidant enzyme activities in kidneys, and urinalyses. CP significantly increased the concentrations of urea and creatinine, and decreased creatinine clearance. It also significantly reduced cortical glutathione concentration and the activity of superoxide dismutase. CP treatment significantly increased urine volume and N‐acetyl‐β‐D‐glucosaminidase activity and significantly decreased osmolarity and protein concentrations. Emodin treatment markedly and significantly mitigated all these effects. Sections from saline‐ and emodin‐treated rats showed apparently normal proximal tubules. However, kidneys of CP‐treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with emodin. The concentration of CP in the cortical tissues was not significantly altered by emodin treatment. The results suggested that emodin had ameliorated CP nephrotoxicity in rats. Pending further pharmacological and toxicological studies emodin may be considered a potentially useful nephroprotective agent.     

姜黄素预处理及缺血后处理对大鼠肾脏缺血再灌注损伤的保护作用

背景：有研究发现姜黄素预处理、缺血后处理对大鼠肾脏缺血再灌注损伤具有保护作用。目的：建立大鼠肾脏缺血再灌注损伤模型,观察姜黄素预处理、缺血后处理、姜黄素预处理联合缺血后处理对大鼠肾脏缺血再灌注损伤的保护作用。方法：60只SD雄性大鼠随机均分为5组,假手术组、肾脏缺血再灌注模型组、姜黄素组、缺血后处理组以及联合处理组。肾脏再灌注24h后,取下腔静脉血测定肌酐和尿素氮。肾组织测定超氧化物岐化酶活性和丙二醛含量,并行苏木精-伊红染色观察各组肾组织病理学变化。结果与结论：与假手术组比较,其余各组肌酐、尿素氮均升高（P〈0.05）。与缺血再灌注模型组比较,姜黄素组、缺血后处理组和联合处理组的肌酐、尿素氮值在再灌注24h后均下降（P〈0.05）。与姜黄素组和缺血后处理组比较,联合处理组的肌酐更低（P〈0.05）。与假手术组比较,缺血再灌注模型组超氧化物歧化酶活性明显降低,丙二醛含量明显升高,差异有显著性意义（P〈0.05）。与缺血再灌注模型组比较,姜黄素组、缺血后处理组和联合处理组的超氧化物歧化酶活性升高,丙二醛含量降低,差异有显著性意义（P〈0.05）。与姜黄素组和缺血后处理组比较,联合处理组的超氧化物歧化酶活性升高,差异有显著性意义（P〈0.05）。与假手术组比较,缺血再灌注模型组肾小管损伤明显;与缺血再灌注模型组比较,姜黄素组、缺血后处理组和联合处理组肾小管损伤减轻明显,与姜黄素组和缺血后处理组比较,联合处理组损伤更轻。说明示姜黄素预处理和缺血后处理联合应用具有协同作用,可以更好的保护大鼠缺血再灌注损伤肾脏。     

The effect of fosfomycin on nedaplatin-induced nephrotoxicity in rats

The effect of coadministration of fosfomycin (FOM) on nedaplatin-induced nephrotoxicity in rats was investigated for 6 days. FOM decreased nedaplatin-induced nephrotoxicity, as shown by reduced blood urea nitrogen (BUN), serum creatinine levels, and urinary excretion of N-acetyl--d-glucosaminidase (NAG). Further, there were fewer histopathological signs of nephrotoxicity in the groups treated with the combination of nedaplatin and FOM as compared with the nedaplatin-alone group. The concentration of nedaplatin was significantly lower in the renal cortex of rats treated with the combination of nedaplatin and FOM as compared with those treated with nedaplatin alone (p < 0.05). In conclusion, the concomitant administration of FOM and nedaplatin may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of nedaplatin.     

Effect of parathyroid hormone activity on gentamicin nephrotoxicity

Dietary calcium (CA++) supplementation attenuates gentamicin nephrotoxicity in rats. It has been proposed that this protective effect results from the ability of Ca++ to interfere with gentamicin binding to renal cell membranes. However, calcium supplementation also suppresses parathyroid hormone (PTH) activity, which may affect gentamicin nephrotoxicity by altering renal brush border phospholipid composition or renal calcium handling. We therefore compared gentamicin nephrotoxicity in PTH-stimulated control rats and parathyroidectomized (PTX) rats. Although their pretreatment serum ionized calcium concentration was significantly higher (1.27 +/- 0.01 vs. 0.88 +/- 0.06 mmol/L; P less than 0.001), PTH-stimulated rats had higher peak renal cortical gentamicin concentrations (543 +/- 20 vs. 395 +/- 49 micrograms/gm; P less than 0.025) and serum creatinine concentrations (3.0 +/- 0.8 vs. 0.9 +/- 0.3 mg/dl; P less than 0.05). Structural injury and depression of renal cortical slice uptake of p-aminohippurate were also less severe in PTX rats. Gentamicin treatment also caused increased urinary Ca++ excretion in control rats (from 2.12 +/- 0.64 mumol/mg creatinine per day [pretreatment] to 16.86 +/- 2.07 mumol/mg creatinine per day; P less than 0.001) but not in PTX rats. Control rats ingesting chow containing a standard Ca++ content (1.2%) resembled PTX rats. These results indicate that PTH stimulation exacerbates gentamicin nephrotoxicity. Increased peak renal cortical gentamicin concentrations in PTH-stimulated rats may be caused by increased gentamicin transport across the brush border as a consequence of PTH-mediated alteration of plasma membrane phospholipid composition, turnover, or both.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of tempol (4-hydroxy tempo) on gentamicin-induced nephrotoxicity in rats

We investigated the effects of tempol (4-hydroxy tempo), a membrane-permeable radical scavenger, on gentamicin-induced renal failure in rats. The rats were given gentamicin (100 mg/kg/day, i.p., once a day); and gentamicin (100 mg/kg/day, i.p.) and tempol (3.5, 7 or 14 mg/kg/day, i.p., once a day). At the end of 7 days, the gentamicin group produced the remarkable nephrotoxicity, characterized by a significantly decreased creatinine clearance and increased serum creatinine, blood urea nitrogen (BUN) and daily urine volume when compared with controls. In control the BUN value was 21.2 +/- 0.07 (mg/100 mL); in comparison, it was 96.9 +/- 6.03 in gentamicin group (P < 0.05). Renal histopathologic examination confirmed acute tubular necrosis in this group. In rats treated with gentamicin and tempol a partial improvement in biochemical and histologic parameters was observed. BUN values were 96.9 +/- 6.03 and 36.3 +/- 2.39 in gentamicin, and gentamicin plus tempol (14 mg/kg) treated groups, respectively (P < 0.05). These results suggest that the administration of tempol may have a protective effect on gentamicin-induced nephrotoxicity in rats.     

Prolonged endotoxemia enhances the renal injuries induced by gentamicin in rats.

The aim of this study was to evaluate the role of chronic endotoxemia in the nephrotoxicity of gentamicin (GM). Saline or Escherichia coli lipopolysaccharide (LPS) was administered to conscious rats by continuous intravenous perfusion (1 mg/kg per day for 7 days) from a subcutaneously implanted osmotic pump. Twenty-four hours after surgery (day zero), treatment with saline or GM (15 mg/kg; intraperitoneally, twice a day) was started for 5 days. Levels of LPS in plasma measured by Limulus amoebocyte lysate activity decreased significantly from days 1 through 8. At days 5 and 8, the cortical concentrations of GM were higher in the LPS-perfused and GM-treated group (LPS plus GM) than they were in the saline-perfused and GM-treated group (saline plus GM) (P less than 0.05). Blood urea nitrogen and serum creatinine remained at normal levels throughout the experiment. A significant increase of cortical tubular cell regeneration was observed in the LPS plus GM animals as compared with regeneration observed in the other groups (saline plus saline, LPS plus saline, and saline plus GM), as measured by [3H]thymidine incorporation into DNA. Moreover, histopathological nephrotoxicity scores showed a synergistic toxic effect between LPS and GM. These results demonstrate that chronic perfusion of low doses of LPS potentiates the nephrotoxicity of GM.     

Role of heme oxygenase-1 in polymyxin B-induced nephrotoxicity in rats

Polymyxin B (PMB) is a cationic polypeptide antibiotic with activity against multidrug-resistant Gram-negative bacteria. PMB-induced nephrotoxicity consists of direct toxicity to the renal tubules and the release of reactive oxygen species (ROS) with oxidative damage. This study evaluated the nephroprotective effect of heme oxygenase-1 (HO-1) against PMB-induced nephrotoxicity in rats. Adult male Wistar rats, weighing 286 ± 12 g, were treated intraperitoneally once a day for 5 days with saline, hemin (HO-1 inducer; 10 mg/kg), zinc protoporphyrin (ZnPP) (HO-1 inhibitor; 50 μmol/kg, administered before PMB on day 5), PMB (4 mg/kg), PMB plus hemin, and PMB plus ZnPP. Renal function (creatinine clearance, Jaffe method), urinary peroxides (ferrous oxidation of xylenol orange version 2 [FOX-2]), urinary thiobarbituric acid-reactive substances (TBARS), renal tissue thiols, catalase activity, and renal tissue histology were analyzed. The results showed that PMB reduced creatinine clearance (P < 0.05), with an increase in urinary peroxides and TBARS. The PMB toxicity caused a reduction in catalase activity and thiols (P < 0.05). Hemin attenuated PMB nephrotoxicity by increasing the catalase antioxidant activity (P < 0.05). The combination of PMB and ZnPP incremented the fractional interstitial area of renal tissue (P < 0.05), and acute tubular necrosis in the cortex area was also observed. This is the first study demonstrating the protective effect of HO-1 against PMB-induced nephrotoxicity.     

Vancomycin enhancement of experimental tobramycin nephrotoxicity.

The influence of vancomycin on tobramycin nephrotoxicity was assessed in male Fischer rats. Treatment groups included controls receiving diluent and groups receiving vancomycin alone at a dosage of 200 mg/kg (body weight) per day, tobramycin alone at a dosage of 80 mg/kg per day, and a combination of vancomycin and tobramycin at the above dosages. All regimens were injected on a twice-a-day schedule. The animals were sacrificed on days 1, 3, 10, 14, 17, and 21. When compared with controls, animals receiving vancomycin alone exhibited no detectable renal toxicity. Compared with the case with controls, tobramycin alone was toxic, as manifested by lower mean animal weights, increased blood urea nitrogen concentrations on days 14 and 17 (P less than 0.005), increased serum creatinine concentrations on days 17 and 21 (P less than 0.005), and the presence of renal cortical tubular necrosis and regeneration. When compared with tobramycin alone, the combination of vancomycin and tobramycin caused earlier and more severe toxicity. By day 10, the magnitude of weight loss, the rise in blood urea nitrogen, and the increase in serum creatinine concentration were all greater in the rats given the combination of vancomycin plus tobramycin than in the animals given tobramycin alone (P less than 0.005). In addition, there was more proximal tubular necrosis and regeneration in rats given vancomycin plus tobramycin compared with those given tobramycin alone. In this animal model, vancomycin alone caused no detectable renal injury, tobramycin alone produced minimal proximal tubular damage, and the combination of vancomycin and tobramycin resulted in a greater degree of kidney injury than observed with tobramycin alone.     

Effect of fasting on temporal variation in the nephrotoxicity of amphotericin B in rats

Evidence for temporal variation in the nephrotoxicity of amphotericin B was recently reported in experimental animals. The role of food in these variations was determined by studying the effect of a short fasting period on the temporal variation in the renal toxicity of amphotericin B. Twenty-eight normally fed and 28 fasted female Sprague-Dawley rats were used. Food was available ad libitum to the fed rats, while the fasted animals were fasted 12 h before and 24 h after amphotericin B injection to minimize stress for the animals. Water was available ad libitum to both groups of rats, which were maintained on a 14-h light, 10-h dark regimen (light on at 0600 h). Renal toxicity was determined by comparing the levels of excretion of renal enzyme and the serum creatinine and blood urea nitrogen (BUN) levels at the time of the maximal (0700 h) or the minimal (1900 h) nephrotoxicity after the intraperitoneal administration of a single dose of dextrose (5%; control group) or amphotericin B (50 mg/kg of body weight; treated group) to the rats. The nephrotoxicities obtained after amphotericin B administration at both times of day were compared to the nephrotoxicities observed for time-matched controls. In fed animals, the 24-h urinary excretion of N-acetyl-beta-D-glucosaminidase and beta-galactosidase was significantly higher when amphotericin B was injected at 0700 and 1900 h. The excretion of these two enzymes was reduced significantly (P < 0.05) in fasting rats, and this effect was larger at 0700 h (P < 0.05) than at 1900 h. The serum creatinine level was also significantly higher (P < 0.05) in fed animals treated at 0700 h than in fed animals treated at 1900 h. Fasting reduced significantly (P < 0.05) the increase in the serum creatinine level, and this effect was larger in the animals treated at 0700 h. Similar data were obtained for BUN levels. Amphotericin B accumulation was significantly higher (P < 0.05) in the renal cortexes of fed rats than in those of fasted animals, but there was no difference according to the time of injection. These results demonstrated that fasting reduces the nephrotoxicity of amphotericin B and that food availability is of crucial importance in the temporal variation in the renal toxicity of amphotericin B in rats.     

七氟醚预处理对大鼠急性肾缺血-再灌注损伤保护作用的实验研究

目的：探索七氟醚对急性肾缺血-再灌注损伤肾功能的保护作用。方法选择健康 SD 大鼠90只,随机分为三组：伪手术组、对照组及七氟醚预处理组,建立肾缺血-再灌注模型,测定各组大鼠平均动脉压（MAP）、二氧化碳分压（PCO2）、血清尿素氮（BUN）、肌酐（Cr）及超氧化物歧化酶（SOD）的变化,HE 染色观察各组大鼠肾组织病理改变。结果随着七氟醚预处理浓度的增加,大鼠 MAP 呈下降趋势,但在七氟醚浓度2％-3％的临床常用剂量范围内,大鼠的 MAP 波动于92．1±6．0 mmHg。各组肾缺血前与再灌注后,PCO2浓度无明显变化。对照组及七氟醚预处理组 BUN 和 Cr 于再灌注后12 h、24 h 均明显高于伪手术组（P ＜0．05）,但七氟醚预处理组再灌注后12 h、24 h 的BUN、Cr 水平均较对照组明显下降（P ＜0．05）。七氟醚预处理组和对照组均较伪手术组血清 SOD 活力减低,但七氟醚预处理组 SOD 活力较对照组高,差异具有统计学意义（P ＜0．05）。肾脏病理观察发现伪手术组肾脏组织结构完整,对照组肾脏外髓部分组织结构严重破坏,而七氟醚预处理组肾脏组织破坏较小,肾小管组织相对完整。结论七氟醚吸入式麻醉能够有效降低 BUN、Cr 水平,保护 SOD 活力,对急性肾缺血-再灌注损伤肾功能具有一定的保护作用。     

Caffeic acid phenethyl ester protects against oxidative stress-related renal dysfunction in rats treated with cyclosporin A

The therapeutic index of cyclosporin A (CsA), an immunosuppressive drug, is limited by its nephrotoxic effect. Oxidative stress is suggested to play a crucial role as pathogenic factors. The present study aimed at investigating the effects of caffeic acid phenethyl ester (CAPE), a phenolic antioxidant, on renal function, morphology, and oxidative stress following CsA treatment. Rats were treated with vehicle, CsA (50 mg/kg), and CsA plus CAPE (10 and 30 μmol/kg) for 10 days. Renal function, histopathology, and tissue malondialdehyde (MDA) and reduced glutathione (GSH) levels were evaluated 24 h after the last treatment. CsA produced nephrotoxicity as indicated by a significant increase in serum creatinine and blood urea nitrogen, but decrease creatinine and urea clearance compared to those treated with vehicle. Severe vacuolations and tubular necrosis were evident in the kidney of CsA-treated rats. CsA also increased renal MDA and decreased GSH content significantly. Administration of CAPE along with CsA restored all the changes caused by CsA. These results clearly demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction and also point to the protective potential of CAPE against CsA nephrotoxicity. The protection afforded by CAPE is mediated, at least in part, through inhibiting renal lipid peroxidation and enhancing or maintaining the antioxidant glutathione content.     

Nephroprotective Potential of Alstonia scholaris in Cisplatin Induced Nephrotoxicity in Experimental Animals

The present investigation was aimed to determine the alterations in antioxidant, biochemical and histopathological parameters in cisplatin (cDDP) induced nephrotoxicity and its protection by treatments with aqueous and ethanolic leaf extracts of Alstonia scholaris. Acute nephrotoxicity was induced by single intra-peritoneal administration of cDDP (12 mg kg⁻¹) in wistar rats. Nephrotoxic rats were treated with quercetin (50 mg kg⁻¹), aqueous and ethanolic leaf extracts (300 mg kg⁻¹) by oral gavage. Cisplatin treatment elevated (P < 0.05) the levels of blood urea nitrogen, creatinine, uric acid, total oxidant status (TOS), oxidative stress index, malondialdehyde (MDA) but lowered (P < 0.05) total plasma proteins, total antioxidant status, total thiols, blood glutathione (GSH) levels and antioxidant enzymes as compared to control. Administrations with ethanolic leaf extract following cDDP exposure restored (P > 0.05) creatinine, albumin, TOS, GSH and activities of antioxidant enzymes in blood and renal tissue. Leaf extracts administration also reduced (P < 0.05) erythrocyte and renal MDA levels following cDDP treatment. The restorations of various antioxidant and renal parameters were also supported by the histopathological findings of renal tissue. Administrations with ethanolic leaf extract have high potential to minimize cDDP induced renal damage as indicated by restoration of biochemical, antioxidant and histopathological alterations in nephrotoxic rats as compared to aqueous extract of A. scholaris.

     

Ascorbic acid and alpha-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 (alpha-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.     

Investigating the protective effects of aged garlic extract on cyclosporin-induced nephrotoxicity in rats

Cyclosporin A (CsA) nephrotoxicity has been described in solid organ recipients and in the patients who were treated for autoimmune diseases. Reactive oxygen species-induced oxidative stress and lipid peroxidations are implicated in the pathophysiology of CsA-induced renal injury. Aged garlic extract (AGE) has been reported to exhibit potent antioxidative and free radical scavenging abilities in various disease conditions. The present study was designed to investigate whether AGE could possibly have a protective effect against nephrotoxicity induced by CsA. Male Wistar rats were treated orally with CsA (50 mg/kg/day), CsA + AGE (0.25, 0.5, 1, and 2 g/kg/day started 3 days before the first dose of CsA), or the vehicle of CsA for a period of 10 days. Blood urea nitrogen, serum creatinine, creatinine clearance, and renal histopathological changes were evaluated after 24 h of the last treatment. CsA caused an increase in blood urea nitrogen and serum creatinine by 117 and 100%, respectively, whereas it decreased creatinine clearance by 78% compared with the vehicle-treated rats (all P < 0.001). AGE treatment (0.5, 1 and 2 g/kg) significantly protected animals against CsA-induced biochemical changes, albeit blood urea nitrogen and creatinine clearance in the 0.5 g/kg AGE treated-animals were only partially restored. Kidney sections taken from CsA-treated rats showed severe vacuolations and tubular necrosis. These histopathological changes were markedly improved by pretreatment of rats with AGE at the dose of 0.5--2 g/kg. The results indicate that AGE ameliorates renal dysfunction and morphological changes induced by CsA, and imply that it could be a beneficial remedy for attenuating the CsA nephrotoxicity.     

Association between increased atrial natriuretic peptide and reduced cisplatin nephrotoxicity in rats.

Plasma atrial natriuretic peptide (ANP) concentrations were monitored in two experimental models of protection from cisplatin nephrotoxicity. Sprague-Dawley rats made diabetic with streptozotocin (65 mg/kg) were protected from cisplatin-induced nephrotoxicity when compared to control rats as indicated by reduced plasma creatinine (0.49 +/- 0.02 vs. 0.9 +/- 0.06 mg/dl; P less than .001) and blood urea nitrogen concentrations (18.51 +/- 1.4 vs. 43.08 +/- 2.1 mg/dl; P less than .001). Plasma ANP was also increased with experimental diabetes (76.5 +/- 8.98 fmol/ml) vs. normoglycemic controls (43.8 +/- 8.9 fmol/ml; P less than .02). When diabetic rats were treated with insulin, the renal protection observed with the diabetic state was reversed (creatinine, 0.70 +/- .05 mg/dl); plasma ANP concentrations were also reduced (52.2 +/- 15.2 fmol/ml). Renal platinum concentrations were significantly lower in the diabetic group and the reversal of diabetic-induced renal protection with insulin was associated with increased renal platinum concentrations. In rats given a single i.p. dose of cisplatin (5 mg/kg), a reduction in cisplatin-induced nephrotoxicity was observed when 5% NaCl was the vehicle of choice compared to that seen in rats given the same dose of drug in 0.9% saline (creatinine, 0.43 +/- 0.07 with 5% NaCl vs. 0.63 +/- 0.03 with 0.09% NaCl). NaCl (5%) administration also resulted in increased plasma ANP concentrations when compared to rats receiving equivalent volumes of 0.9% NaCl (88.4 +/- 6.2 vs. 50.5 +/- 5.6 fmol/ml, respectively). These data suggest that increased endogenous ANP may be a mechanism of renal protection common to both experimental diabetes and hypertonic saline administration. Chronically increased ANP may prevent renal accumulation of platinum in the kidney.     

Evidence of oxidative stress in the renal cortex of diabetic rats: favourable effect of vitamin E

The aim of this study was to determine whether there are any disturbances of red/ox balance in the renal cortex of rats during the course of experimental diabetes. In the renal cortex of rats with streptozotocin-induced diabetes, the activity of superoxide dismutase (SOD) isoenzymes, glutathione peroxidase (GSH-Pox). glutathione S-transferase (GST) and glutathione reductase (GSH-RED) was measured in the 5th, 10th and 15th weeks of diabetes. Free radical cell damage was assessed on the basis of malonyldialdehyde (MDA) concentration. The influence of lipophilic antioxidant vitamin E on these analytes was also studied. An increase in MDA concentration in the 10th and 15th weeks of diabetes correlated significantly with plasma glucose concentration (r=0.47; p<0.001). Moreover, MDA concentration was influenced by time (+); p<0.001, diabetes (+); p<0.001, vitamin E (-) p<0.001 (ANOVA). Plasma creatinine concentration in rats was elevated by diabetes (p<0.001), whereas vitamin E decreased the concentration (p<0.05). Vitamin E lowered the activity of GSHPox (p<0.001) and GST (p<0.01) (ANOVA). Our results indicate that during experimental diabetes, disturbances of red/ox balance lead to disturbance in renal function manifested as increased creatinine blood concentration. We suggest that oral supplementation of vitamin E protects the renal cortex of rats during experimental diabetes.