Protective effect of Moringa oleifera leaves against gentamicin-induced nephrotoxicity in rabbits

Oxidative stress due to abnormal production of reactive oxygen species has been implicated in the nephrotoxicity induced by gentamicin. The nephroprotective effect of aqueous-ethanolic extract of Moringa oleifera leaves (150 and 300 mg/kg) was evaluated against gentamicin-induced (80 mg/kg) renal injury in rabbits. Serum urea and creatinine levels were evaluated as the markers of renal nephrotoxicity. At the end of the experiment, the kidneys of rabbits were excised for histological examinations and determination of lipid peroxidation levels. Serum urea and creatinine levels were reduced in the M. oleifera (150 and 300 mg/kg) plus gentamicin treated groups. On histological examinations, kidney of intoxicated rabbits groups which received M. oleifera extract showed reparative tendencies. A highly significant (p < 0.01) elevation was observed in lipid peroxidation (LPO) level in the kidneys of gentamicin-intoxicated rabbits whereas combined treatment of M. oleifera and gentamicin group showed a highly significant (p < 0.01) depletion in LPO. The present study indicates that aqueous-ethanolic extract of M. oleifera leaves attenuates renal injury in rabbits treated with gentamicin, possibly by inhibiting lipid peroxidation.     

Protective effects of nigella sativa against gentamicin-induced nephrotoxicity in rats

The aim of this study was focused on investigating the possible protective effect of NS against GS-induced nephrotoxicity. Twenty four Wistar-albino rats were divided into four equal groups as follows: control group, GS group (100 mg/kg intraperitoneal – i.p.), NSL+GS group (0.2 ml/kg+100 mg/kg i.p.) and NSH+GS group (0.4 ml/kg+100 mg/kg i.p.). Plasma creatinine and urea levels significantly increased as a result of nephrotoxicity in the GS group. Also, creatinine and urea levels significantly decreased in NSL+GS and NSH+GS groups. In the GS group, plasma MDA and NO levels increased significantly (p<0.05) and erythrocyte SOD and GSH-Px activities decreased significantly (p<0.05) when compared with control group. NS administration with GS injection resulted in significantly decreased MDA and NO generation and increased SOD and GSH-Px activities when compared with GS group. Proximal tubular necrosis, vacuolation, desquamation and degeneration in epithelial cells of the proximal tubules, hyaline casts in tubular lumen, mononuclear cell infiltration, glomerular and basement membrane alterations were histopathologically detected in the kidneys of the GS group. Co-treatments with NS (low and high dose) considerably decreased the renal damage when compared with the GS group. In conclusion, NS acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GS both in the biochemical and histopathological parameters.     

Protective effects of corn silk extract administration on gentamicin-induced nephrotoxicity in rat

The objective of this study was to evaluate effect of corn silk against gentamicin (GM)-induced nephrotoxicity. Sixty Wistar rats were divided into ten equal groups as follow: (1) control group, 0.1 ml/kg given intraperitoneally (i.p.) per day of isotonic saline. (2) GM group, 100 mg/kg i.p. per day of GM. (3) corn silk groups (3–6), 200, 300, 400, and 500 mg/kg, i.p. (4) Corn silk + GM groups (7–10), corn silk extract was injected the same as corn silk groups and after1 h, 100 mg/kg GM was injected i.p. to rats. All animals were treated for 8 days. Plasma creatinine and urea levels significantly increased in GM group. Corn silk administration (200 and 300 mg/kg) with GM injection significantly decreased serum creatinine, but not urea, levels compared with GM group. Acute tubular necrosis (ATN), hyaline casts in tubular lumen, interstitial nephritis, and glomerular changes were histopathologically detected in the GM group. Co-treatment of corn silk with GM considerably decreased the interstitial nephritis, but not ATN and hyaline casts formation, compared with the GM group. Also, high dose of corn silk caused hyaline cast formation, apoptosis, congestion, and swelling of renal tubules. In conclusion, the results showed that corn silk may ameliorate nephropathy during prolonged therapeutic use of GM and related aminoglycosides.     

Dietary composition alters gentamicin-induced nephrotoxicity in rats

Previous studies have shown temporal variations in gentamicin-induced renal toxicity characterized by a peak when administered during the resting period and a trough during the active period. This time-dependent toxicity was also altered according to the macronutrient composition of dietary regimens offered to female rats. In the present study, adult female Sprague-Dawley rats were adapted to semipurified isocaloric diets containing 20% casein or soy-protein (10% fat each) or to a standard chow diet (18.1% mixed proteins; 4.5% fat). The animals were then chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day ip) or a saline solution administered in the middle of their resting period (1200 h) or in the middle of their activity period (0000 h). Body weights of rats injected in the middle of their resting period decreased over the last 6 days of gentamicin treatment. Total 12-h light and 12-h dark food intakes were decreased in gentamicin-treated rats. Rats fed the standard chow diet had significantly lower corticocellular regeneration, serum creatinine and blood urea nitrogen compared to those fed the casein- and soy-containing diets. The present study demonstrates that chronic gentamicin-induced renal toxicity varies temporally according to the time of administration and that a mixed protein diet containing a lower fat level can protect against gentamicin-induced nephrotoxicity.     

Dietary protein level alters gentamicin-induced nephrotoxicity in rats

Aminoglycosides (AG) such as gentamicin are antimicrobial drugs widely used in the hospital setting due to their efficacy in the treatment of severe gram-negative bacterial infections. However, all AG have the potential to cause nephrotoxicity. Two studies have been conducted (1) to assess the protein level of a diet that would give the best renal outcome with gentamicin administration, and (2) to get a better idea about the rhythms of food ingestion associated with the different protein levels. Adult female Sprague–Dawley rats fully adapted to a standard chow diet, the standard chow with 20% or 55% added casein were chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/day, i.p.) or a saline solution. Food ingestion patterns of rats were recorded every hour using a Diet Scan system and gentamicin nephrotoxicity indices were measured. The second study used rats that were fed the same diets and given a sham injection. Corticosterone was assayed to quantify the stress of the animals. Results showed that chronic gentamicin treatment leads to a decrease in food intake and flattening of the rhythms of food ingestion. Also, chow feeding and the 20% casein diet were found to be more protective against gentamicin-induced nephrotoxicity than the 55% casein diet. Therefore, while a protein-rich diet can be protective against gentamicin-induced nephrotoxicity, the present study demonstrates that a diet too high in protein might rather be harmful to the kidneys.     

Effects of the calcium-channel blocker diltiazem on gentamicin-induced nephrotoxicity in rats

Injection of diltiazem (40 mg/kg/d) to gentamicin (75 mg/kg/d = G 75 or 100 mg/kg/d = G 100) treated rats enhances aminoglycoside-induced nephrotoxicity. As a result of this combination, acute renal failure becomes systematic and is often irreversible. The lesion is of tubular origin and is characterized by a large increase in the urinary N-acetyl-beta-D-glucosaminidase (u-NAG) activity and its NAG-B isoenzyme level. The phenomenon is twice as marked with G 75 (u-NAG x 6.8, NAG-B x 2.2) as with G 100 (u-NAG x 3.1, NAG-B x 1.1). The effect seems to be attenuated if diltiazem is administered as a preventive treatment or in drinking water. As well as its diuretic properties, diltiazem may aggravate the renal toxicity of gentamicin by reducing the proximal tubular availability of calcium. Diltiazem inhibits reabsorption and behaves like a non-competitive inhibitor of calcium. This deficiency favours the proximal tubular binding and the non-specific penetration of gentamicin in the cytosol and cellular organelles (microsomes, mitochondria). The tubular toxic symptoms which ensure (inactivation of membranaceous enzyme, reduction of microsomal protein synthesis and ATP level, decreased of solute reabsorptive flux) lead in turn to proximal tubular necrosis and acute renal failure.     

Increased renal glomerular endothelin-1 release in gentamicin-induced nephrotoxicity

Gentamicin-induced acute renal failure is characterized by a decrease in renal plasma flow and creatinine clearance. Endothelins (ET) are potent renal vasoconstrictors. The aim of this work is to assess the role of ET-1 in gentamicin-induced renal failure. Renal glomerular release of ET-1 was measured in rats with gentamicin-induced nephrotoxicity (100 mg/kg/day, s.c. for 2, 4 or 6 days). Glomeruli were isolated and incubated for 24 h in RPMI-1640. Glomerular supernatant and plasma concentration of ET-1 were measured by RIA. Renal failure was assessed by insulin, para-aminohippuric and creatinine clearance and histological studies. Gentamicin induced a dose number-dependent increase in plasma creatinine and a decrease in creatinine clearance. This was accompanied by a marked decrease in inulin and para-aminohippuric acid clearance, as well as by a marked tubular necrosis, without alterations in glomerular structures. Plasma ET-1 concentration and glomerular ET-1 release were also increased in gentamicin-treated rats. When 10-5 M gentamicin was added to control glomeruli, ET-1 production was not modified (36.4 +/- 2.2 vs. 35.2 +/- 1.7 pg/ml/24 h). All these results suggest that elevated ET-1 plasma levels and increased glomerular release of ET-1 could mediate, at least in part, the decrease in glomerular filtration rate observed in gentamicin-induced ARF.     

Effects of co-supplementation of vitamins E and C on gentamicin-induced nephrotoxicity in rat

Gentamicin (GM) is an effective antibiotic against severe gram-negative infections. However it can produce nephrotoxicity in human. Reactive oxygen species (ROS) have been proposed as the causative factors of the renal side effects the drug. This study was performed to investigate the protective role of antioxidant vitamins against GM-mediated nephropathy in an in situ model of isolated rat kidney. Male Sprague-Dawley rats were randomly assigned to one of the following groups of seven rats: group 1 (Control) was perfused with Tyrode solution; group 2 (GM), 200 microg ml(-1) GM was added to the perfusate; group 3 (GM + Vit C), as group 2 with vitamin C added to the drinking water for 3 days (200 mg l(-1)) and to the perfusate (100 mg l(-1)); group 4 (GM + Vit E), as group 2 with vitamin E (100 mg (100 g body weight)(-1), i.m.) injected 12 h before the start of the experiment; group 5 (GM + Vit C + Vit E) as group 2 with vitamin E and C co-administered (concentrations and conditions as in groups 3 and 4). To compare the groups, urinary lactate dehydrogenase (LDH), N-acetyle-beta-D-glucosaminidase (NAG) and alkaline phosphatase (ALP) activities, inulin clearance (glomerular filtration rate, GFR) and renal tissue glutathione (GSH) content were measured. GM caused a significant nephrotoxicity demonstrated by an increase in urinary LDH, NAG and ALP activities. Reduction in GSH content and a marked decrease in GFR were observed compared to controls. Vitamin C inhibited the GM-induced increase in urinary enzyme activities but did not show a significant effect on the GSH content or GFR. Vitamin E prevented the GM-induced reduction in GSH level without a significant improvement in GFR. Co-administration of vitamins C and E significantly prevented the GM-induced nephrotoxicity demonstrating by preservation of GFR and GSH levels and prevention of increase in urinary enzyme activities. We conclude that co-administration of moderate doses of vitamins C and E has beneficial effects on renal preservation in GM-induced nephrotoxicity.     

Model of gentamicin-induced nephrotoxicity and its amelioration by calcium and thyroxine

The exact mechanism of gentamicin-induced acute renal failure is presently unknown; various mechanisms have been proposed but there is no proposed commonality between them. In animals, dietary calcium loading and L-thyroxine administration have been shown to ameliorate toxicity, with again no common process. A mechanism of competitive displacement of calcium and other cations from anionic phospholipids at the plasma and organelle membrane level, resulting in a decrease in Na+ -K+ ATPase, adenylate cyclase, mitochondrial function and ATP production, protein synthesis, solute reabsorption and overall cellular function is proposed. A further proposal is dietary calcium loading and thyroxine (which increases intracellular calcium) reverse gentamicin-induced acute renal failure by increasing the calcium and solute flux, thereby competitively inhibiting the primary lesion: anionic phospholipid binding.     

鹿茸水提物减轻顺铂所致的小鼠肾损伤

目的:探讨梅花鹿二杠茸和三岔茸水提物对顺铂(CDDP)所致小鼠肾损伤的影响。方法:采用灌胃给药方式,用顺铂(15 mg/kg)诱导小鼠肾损伤模型,测定小鼠肾脏指数(KI)、血清肌酐(SCr)、血尿素氮(BUN)、肾脏组织中超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量,并对肾脏组织进行HE染色,观察肾脏病理学变化,研究梅花鹿二杠茸和三岔茸的水提物各剂量对小鼠肾损伤的影响。结果:与顺铂组相比,各剂量鹿茸水提物可显著降低CDDP诱导肾损伤小鼠SCr、BUN水平及肾脏MDA含量,提高SOD和GSH-Px的活性(P0.05);明显改善肾组织病理学形态,减轻CDDP对肾小管上皮细胞的损伤程度,且同等浓度下,与三岔茸相比,二杠茸水提物能更好地改善肾功能及减轻病理损伤。结论:鹿茸水提物减轻顺铂引起的小鼠肾损伤,其作用机制可能与鹿茸水提物增强小鼠肾脏组织的抗氧化能力有关。     

Protective effect of Phyllanthus niruri against cyclosporine A-induced nephrotoxicity in rats

Phyllanthus niruri (Euphorbiaceae) is a popular plant in folk medicine, whole plant, fresh leaves, and fruits are used in the treatment of various diseases. In the present study, nephroprotective potential of aqueous extract of P. niruri was investigated against cyclosporine A (CsA) induced changes in kidney of Wistar rats. Nephrotoxicity was induced by oral administration of CsA (25 mg/kg/b.w.) dissolved in olive oil for a period of 21 days. Nephrotoxicity induced rats were treated with aqueous extract of P. niruri (200 mg/kg/b.w.) for a period of 21 days. Levels of serum creatinine and blood urea nitrogen, renal marker enzymes in serum and different enzymic and non-enzymic antioxidants, lipid peroxidation products, as well as ATPases in kidney homogenates were measured in normal, control (toxicity induced), and P. niruri treated rats. Histopathological studies were also been carried out. Administration of CsA increased the serum levels of creatinine and blood urea nitrogen, alkaline phosphatase, alanine aminotransaminase, and lactate dehydrogenase thereby indicating damage to kidneys. Increased lipid peroxidation and a decrease in antioxidants enzymes were observed in toxicity-induced rats. The levels of membrane-bound ATPases were also significantly altered. Upon administration of P. niruri, the levels of serum creatinine and blood urea nitrogen and also lipid peroxidation were found to be markedly reduced. Renal antioxidant defense systems, such as superoxide dismutase, catalase, glutathione peroxidase activities and reduced glutathione, and vitamins e and c, depleted by cyclosporine A, were restored to normalcy by treatment with the extract. The drug also effectively attenuated renal dysfunction and normalized the altered renal morphology and also restored the activities of renal ATPases. The results suggest that the nephroprotective effect of P. niruri could be due to the inherent antioxidant and free-radical scavenging principle(s) contained in the extract. In conclusion, our study indicates that P. niruri through its antioxidant activity effectively salvaged CsA induced nephrotoxicity.     

Protective role of aminoguanidine on gentamicin-induced acute renal failure in rats

The toxicity of aminoglycosides including gentamicin (GEN), the most widely used drug in this category, is believed to be related to the generation of reactive oxygen species (ROS) in the kidney. Aminoguanidine (AG) is known as an effective antioxidant and its free radical scavenger effects may protect GEN-induced acute renal failure (ARF). Therefore, this study was focused on investigating the possible protective effect of AG against GEN-induced nephrotoxicity in an in vivo rat model. We investigated the effects of AG on GEN-induced changes in renal tissue malondialdehyde (MDA) levels; nitric oxide (NO) generation; glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT) activities; glutathione (GSH) content; serum creatinine (Cr) and blood urea nitrogen (BUN) levels. Morphological changes in the kidney were also examined using light microscopy. GEN administration to control group rats increased renal MDA and NO levels but decreased GSH-Px, SOD, CAT activities and GSH content. AG administration with GEN injection resulted in significantly decreased MDA, NO generation and increased GSH-Px, SOD, CAT activities and GSH content when compared with GEN alone. Serum levels of Cr and BUN significantly increased as a result of nephrotoxicity. Also, AG significantly decreased Cr and BUN levels. Morphological changes in the kidney, including tubular necrosis, intracellular edema, glomerular and basement membrane alterations were evaluated qualitatively. Both biochemical findings and histopathological evidence showed that administration of AG reduced the GEN-induced kidney damage. We propose that AG acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GEN both at the biochemical and histological level.     

淫羊藿、虫草菌丝、黄芪防治庆大霉素所致急性肾损害的实验研究

采用腹腔内注射庆大霉素造成大鼠急性肾小管损伤模型,发现中药淫羊藿、虫草菌丝和黄芪均可以减轻庆大霉素所致的大鼠肾小管及肾间质的损伤,并可拮抗庆大霉素对大鼠肾皮质Na~+-K~+-ATP酶的抑制作用。     

Electron microscopic evaluation of milk thistle,chicory, and vitamin E effects on gentamicin-induced nephrotoxicity in rat

Gentamicin is an aminoglycoside with nephrotoxic effects; however, it seems that antioxidants such as vitamin E, milk thistle, and chicory extracts can reduce these effects. To test this, 60 male Wistar rats (200–250 g) were randomly allocated into six groups (n = 10). Each animal received intraperitoneal injections daily for 14 days: group 1—distilled water (1 ml) (control); group 2—gentamicin; group 3—gentamicin and milk thistle; group 4—gentamicin and chicory; group 5—gentamicin and vitamin E; and group 6—gentamicin, vitamin E, milk thistle, and chicory. At termination, blood was taken, to measure the serum levels of blood urea nitrogen (BUN) and creatinine, and the kidneys were taken, sampled, and processed for examination using a transmission electron microscope. Using milk thistle, chicory and vitamin E all showed a decrease in both dense bodies and damage to the nucleus. These observations were more pronounced in the group that received milk thistle, chicory, and vitamin E together. The levels of BUN and creatinine in all treatment groups were significantly lower compared to those of the gentamicin group (group 2). In conclusion, milk thistle, chicory, and vitamin E, individually, can reduce kidney damage caused by gentamicin, but they have a greater effect in reducing damage if used together.     

Dose-related protecting effects of vitamin C in gentamicin-induced rat nephrotoxicity: a histopathologic and biochemical study

Gentamicin remains the mainstay in treatment of gram-negative infections, despite its potential ototoxicity and nephrotoxicity. In this study, we investigated dose-related protecting effects of vitamin C against gentamicin-induced rat nephrotoxicity. Hence, 50 male albino Wistar rats were randomly divided into five equal groups to receive a corresponding dose of either normal saline as control, vitamin C (200 mg/kg/bw, i.m.) or gentamicin alone (80 mg/kg/bw, i.m.) or in combination with vitamin C at low dose (200 mg/kg/bw, i.m.; LVG) and high dose (600 mg/kg/bw, i.m.) for 9 days. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in oxidative stress in renal tissues and plasma and a concomitant decrease in the creatinine clearance and renal blood flow as result of early hemodynamic toxicity. Histopathological examinations revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies showed protecting effects of supplemented vitamin C at a high dose, including slowdown in the urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and the ATPase activity up to 50% when compared to controls and low-dose rats (LVG). In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin C consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin C prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.     

Exaggerated response to gentamicin-induced nephrotoxicity in Sprague-Dawley rats: identification of a highly sensitive outlier population

A number of factors have been shown to predispose patients treated with aminoglycosides to nephrotoxicity. In a previous study in our laboratory investigating the interaction of prior renal dysfunction with gentamicin toxicokinetics, 9.4% of rats in all treatment groups were relatively more sensitive to gentamicin-induced nephrotoxicity. To determine if these outliers had an underlying disease or physiological abnormality, serum was collected from 99 Sprague-Dawley rats prior to daily treatment with 75 mg/kg gentamicin for seven days. Urea nitrogen, creatinine, Na, K, Ca, Mg, P, total protein, albumin, aspartate transaminase, serum osmolality, total white and red blood cell count, hematocrit, hemoglobin, blood gases, and thyroxine were measured. Blood was collected one and four hours after the first dose of gentamicin for pharmacokinetic analysis. Elevations in post-treatment creatinine and nitrogen were significantly greater in the outliers (4.10 +/- 0.24 mg/dl (n = 12) vs 1.92 +/- 0.06 mg/dl (n = 87) and 146.4 +/- 7.2 mg/dl (n = 12) vs 71.5 +/- 2.0 mg/dl (n = 87); both p = 0.0001) and served as criteria for identifying this subgroup. Post-treatment creatinine and urea nitrogen were not normally distributed in the entire study population. However, when the population was divided into normal and sensitive subgroups, both subgroup values were normally distributed. The gentamicin pharmacokinetic profiles were similar in both groups. Postmortem histopathology showed significant increases in tubular casts and tubular necrosis (p = 0.01) in the sensitive rats, compared to the normally responding subgroup.(ABSTRACT TRUNCATED AT 250 WORDS)     

Protective effects of 2-deoxy-D-glucose on nephrotoxicity induced by cyclosporine A in rats

Objective: This study aims to explore the protective effect mechanism of 2-deoxy-D-glucose on nephrotoxicity of cyclosporin A in vivo. Method: Renal toxicity of SD rats model induced by CsA was established. Serum creatinine, blood urea nitrogen, urine NAG, GSH and MDA were determined and the histopathological changes of rat renal cortex were observed to explore the protective effects of 2-DG on CsA-induced nephrotoxicity. Results: Serum creatinine, BUN and urinary NAG of rats were significantly changed in experimental groups. Pathological results showed that there was obvious renal tubular injury in model group, however, the renal injury was significantly reduced in pre-treated with 2-DG. Conclusions: 2-DG had obvious protective effect on nephrotoxicity especially with high dose. This protective effect could be related to the reduction of ROS induced by CsA. However, 2-DG had no effect on the expression of RIP3.     

Antioxidant preserving effects of l-arginine at reducing the hemodynamic toxicity of gentamicin-induced rat nephrotoxicity: pathological and biochemical findings

Nephrotoxicity results from an abrupt decline in glomerular functions of the kidney and is regarded as a major cause of concern for limiting therapeutic uses of gentamicin in hospital settings. Recent evidences suggest that both endothelial nitric oxide synthesis (eNOS) and inducible NOS (iNOS)-derived nitric oxide (NO) vasodilators reduce renal toxicity, restoring normal glomerular functions and hemodynamic stability, but this has not been adequately investigated in gentamicin nephrotoxicity. To determine the isoform of NOS that plays a predominant role in the control of glomerular vasodilation under the oxidative stress of nephrotoxicity, we conducted a controlled, randomized study in five equal groups of ten Sprague–Dawley rats. All animals were given a corresponding dose of either normal saline, only l-arginine, only gentamicin, or a combination thereof with and without N-3-aminomethyl benzylacetamidine (a selective iNOS inhibitor, 1400W) for 9?days. After 6?days, gentamicin-treated rats developed nephrotoxic alterations evident by a significant fall in renal blood flow and glomerular filtration rate, increased urinary excretion of gamma glutamyl transpeptidase and serum concentration of inflammatory interleukins (IL-6 and IL-8) as well as a decrease in the tissue antioxidant activity of superoxide dismutase. Changes in these biochemical variables were completely inhibited by supplemented l-arginine up to 9?days. However, a combination of 1400W partially removed protective effects of l-arginine on the glomerular hemodynamics of the kidney. Our results suggest that at irradiation of eNOS developed by increased oxidative process, administration of l-arginine increases iNOS-derived NO production and glomeruli infiltration on its direct antioxidant effects counteracting the undesirable effects of peroxynitrite formation on the kidney.