Protective Effects of Pentoxifylline Treatment on Gentamicin-Induced Nephrotoxicity in Rats

Gentamicin (GM) is a widely used antibiotic against serious and life-threatening infections, but its usefulness is limited by the development of nephrotoxicity. Thus, the present study was undertaken to determine if pentoxifylline could protect the kidney in this experimental model. Thirty male Wistar rats were used. The animals were divided into three groups, each with 10 animals. The GM group of animals was treated daily with gentamicin in a dose of 100 mg/kg for eight days. The GMP group of animals was treated daily with pentoxifylline in a dose of 45 mg/kg and the same dose of gentamicin as the GM group for eight days. The control group received 1 mL/day saline intraperitoneally. For histological analysis, 5 μm-thick sections were stained with hematoxylin and eosin (HE), periodic acid Schiff (PAS), and Jones methenamine silver. The morphometric parameters included were glomerular area, major and minor axis, perimeter, diameter, roundness, and mean optical density. Biochemical analyses were used to determine concentrations of blood urea, serum creatinine, sodium, and potassium. In the GM group of rats, glomerular basement membrane was diffusely and unequally thickened with polymorphonuclear leukocyte infiltration, and coagulation-type necrosis and vacuolization of cytoplasm of proximal tubules epithelial cells were observed. In the GMP group of rats, glomeruli were slightly enlarged with thickened basement membrane in some segments but without coagulation-type necrosis of proximal tubules epithelial cells. Blood urea and serum creatinine concentration in the GM group were significantly elevated in comparison with the GMP group, while the potassium level was decreased. The present study indicated that pentoxifylline could provide a marked protective effect against gentamicin-induced acute renal failure, most likely mediated by vascular decongestion.     

Beneficial Effects of Calcium Oral Coadministration in Gentamicin-Induced Nephrotoxicity in Rats

Abstract

Frequent therapeutical use of an aminoglycoside antibiotic gentamicin (GM) is limited by its nephrotoxic effects often characterized by both morphological and functional alterations of kidney leading to acute renal failure. The aim of this study was to examine the effect of dietary calcium supplementation on GM-induced nephrotoxicity in rats. Experiments were performed on 30 adult male Wistar rats divided into three groups of 10 animals each. G-group received GM intraperitoneally at a dose of 100 mg/kg; GCa-group received the same dose of GM concomitantly with 1 g/kg calcium carbonate given orally; and C-group, serving as control, received 1 mL/day of normal saline. All groups were treated during 8 consecutive days. Quantitative evaluation of GM-induced structural and functional changes of kidney was performed by histopathological, morphometrical, and biochemical analyses. Compared with control, G-group of rats were found to have diffusely and unequally thickened glomerular basement membrane with neutrophil cells infiltration. In addition, vacuolization of cytoplasm of proximal tubule cells with coagulation-type necrosis was observed. These GM-induced pathological lesions were significantly reduced in the rats of GCa-group. Morphometric analysis revealed statistically significant differences in the size of glomeruli (area, major and minor axes, perimeter), optical density, and roundness of glomeruli (p < 0.05) between G and GCa groups. Biochemical analysis showed significant elevation in blood urea and serum creatinine concentrations, whereas potassium concentration was lowered in G-group compared with the other groups (p < 0.01). It is concluded that oral supplementation of calcium during treatment with GM resulted in significant reduction of morphological and functional kidney alterations.     

Renoprotective Effect of Grape Seed Extract against Oxidative Stress Induced by Gentamicin and Hypercholesterolemia in Rats

Abstract

Rationale: Kidneys are dynamic organs and represent one of the major systems maintaining the body homeostasis; they are affected by many chemicals and drugs. Grape seed extract (GSE) has been targeted to prevent drug-induced renal toxicity. Objectives: This study investigates the possible renoprotective effect of GSE against oxidative stress, renal impairment, and hypercholesterolemia (HC) induced by gentamicin (GM) and cholesterol-enriched diet. Seventy adult male Wistar rats (160 ± 10 g) were divided into seven groups: (1) served as control, (2) GSE, (3) GM, (4) GSE + GM, (5) hypercholesterolemic (HC) group, (6) GM + HC group, and (7) GM + HC + GSE. Kidney functions, inflammatory mediators, cytokines, lipid profile, nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and oxidative and antioxidative stress parameters were assessed in all groups. Main findings: GM induced renal dysfunction, which was exacerbated by the presence of HC as confirmed by laboratory determinations. Administration of GSE attenuated the renal toxicity evidenced in significant reduction in elevated kidney function, inflammatory cytokines as well as lipid profile, NO, cGMP, enzymatic, and nonenzymatic antioxidants. Conclusion: Administration of GSE simultaneously with GM attenuated oxidative stress, diminished renal toxicity, and improved lipid profile induced by GM and HC.     

Effects of Aulosira fertilisima against Cisplatin-Induced Nephrotoxicity and Oxidative Stress in Rats

Oxidative stress due to abnormal production of reactive oxygen molecules (ROM) is believed to be involved in the etiology of toxicities of many xenobiotics. Evidence suggested that ROM is involved in the nephrotoxicity of a widely used synthetic anticancer drug cisplatin. The nephroprotective effects of ethanol extract of Aulosira fertilisima Ghose (EEA) was evaluated using cisplatin (5 mg/kg^?1 i.p.)-induced renal damage in rats. EEA showed higher significant effect on DPPH radical scavenging activity as compared with methanol extract of A. fertilisima (MEA) and water extract of A. fertilisima (WEA). Thus, EEA was selected for further in vivo studies. The serum urea and creatinine levels in the cisplatin alone-treated group were significantly elevated with respect to normal group of animals. The levels were reduced in the EEA (100 mg/kg, p.o) plus cisplatin-treated groups. Renal oxidative stress was determined by renal TBARS, CD and reduced glutathione levels, and by enzymatic activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione transferase (GST). A single dose of cisplatin-produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic EEA treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the study indicated that A. fertilisima significantly and dose-dependently protected the nephrotoxicity induced by cisplatin. This protection is mediated either by preventing the cisplatin-induced decline of renal antioxidant defense system or by their direct free radical scavenging activity.     

Atorvastatin Prevents Gentamicin-Induced Renal Damage in Rats through the Inhibition of p38-MAPK and NF-kB Pathways

Background and aims. Gentamicin (GM) is still considered to be an important antibiotic against life-threatening, gram-negative bacterial infections despite its known nephrotoxic effects. We aimed to evaluate the potential protective effect of atorvastatin (ATO) against GM-induced nephrotoxicity in rats. Materials and methods. The rats were randomly divided into five groups of six animals each: control, GM (100 mg/kg/day), ATO (10 mg/kg/day), GM + ATO, and GM + Vehicle. Kidney function tests, tissue oxidative stress parameters, and histopathological and immunohistochemical studies clarified GM nephrotoxicity. Results. GM caused a marked reduction in renal functions and increased oxidative stress parameters. Histopathological examination revealed tubular necrosis especially in the renal cortex in GM rats. On immunohistochemical evaluation, GM rat showed more intense expressions of mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF‐kB), and inducible nitric oxide synthase (iNOS) compared with control. Kidney function tests and tissue oxidative stress parameters were normalized in the GM + ATO group. Histopathological and immunohistochemical pictures were also greatly ameliorated. Conclusions. ATO acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GM via the inhibition of MAPK and NF-kB signaling pathways and iNOS expression.     

Effects of Pomegranate Juice on Hyperoxaluria-Induced Oxidative Stress in the Rat Kidneys

To evaluate the role of the inducible nitric oxide synthase (iNOS), selective nuclear factor-kB (NF-kB), and p38-mitogene-activated protein kinase (p38-MAPK) on hyperoxaluria-induced oxidative stress and stone formation in rat kidneys. The rats were divided into five groups: group 1, control group; group 2: ethylene glycol (EG) group; group 3: EG?+?pomegranate juice (PJ)-low group; group 4: EG?+?PJ-middle group; group 5: EG?+?PJ-high group. Rats were sacrificed on 7, 15, and 45 days. The iNOS expression, p65-NF-kB and p38-MAPK activity, and oxidative stress markers were evaluated in the kidney. Crystal depositions were evident on day 7, and mild and severe crystallization were observed on day 15 and 45 in EG group, respectively. There was limited or no crystal formation in rats in both middle- and high-dose PJ groups when compared to low-dose PJ group. Crystal depositions, iNOS, p38-MAPK and p65-NF-kB activity, and oxidative stress markers were found to be decreased by middle- and high-dose PJ treatment. PJ was found to have inhibitory effects on renal tubular cell injury and oxidative stress caused by oxalate crystals by reducing ROS, iNOS, p38-MAPK, and NF-kB expression.     

Effects of Different Doses of Hyperbaric Oxygen on Cisplatin-Induced Nephrotoxicity

Cisplatin, an effective antineoplastic agent, frequently induces acute renal failure in animals and humans. Hyperbaric oxygen (HBO) has been shown to prevent cisplatin-induced nephrotoxicity in rats. This study investigated the effect of two different HBO regimes on renal functions, oxidative stress, and histopathological changes in rat kidneys after cisplatin treatment. Wistar rats were divided into five groups: control, HBO, cisplatin, cisplatin plus once daily HBO, and cisplatin plus twice daily HBO. Cisplatin was given as a single intraperitoneal dose of 6 mg/kg, and HBO was applied for 60 min at 2.5 atm for six days. HBO alone did not alter any biochemical parameters or histopathological findings compared with the control group. Cisplatin increased serum urea and creatinine levels and caused severe histopathological injury. In addition, cisplatin increased lipid peroxidation and impaired superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in kidney tissue. Once daily HBO after cisplatin treatment slightly reduced serum urea and creatinine levels and attenuated histopathological injury. HBO also reduced lipid peroxidation and increased SOD and GSH-Px activities significantly. Although twice daily HBO was determined to be more effective than once daily HBO on oxidative stress parameters, it increased serum creatinine levels and histopathological injury compared with the cisplatin group. It was concluded that HBO alone does not induce nephrotoxicity and oxidative stress in rat kidneys; once daily HBO may prevent cisplatin-induced nephrotoxicity, an effect that is partially mediated by the modification of oxidant/antioxidant systems in the kidneys; and twice daily HBO potentiates cisplatin nephrotoxicity by a ROS-independent mechanism.     

Kidney damage after renal ablation is worsened in endothelial nitric oxide synthase -/- mice and improved by combined administration of L-arginine and antioxidants

Aim Reduction in nitric oxide (NO) levels during kidney failure has been related to the reaction of NO with superoxide anions to yield peroxynitrite which possesses the biological activity responsible for renal damage. However, stimulation of the NO pathway ameliorates the progression of kidney failure. Thus, it is unclear whether NO prevents or acts as the compound responsible for the cytotoxicity observed during kidney failure. Methods We evaluated the development of kidney failure in animals that were wild type and deficient in endothelial NO synthase (eNOS (?/?)) and tested the effects of an antioxidant treatment and NO precursors on the generation of superoxide anion and kidney failure parameters. Results In wild‐type mice, five‐sixths nephrectomy increased proteinuria from 3.0 ± 0.35 to 14.5 ± 0.76 mg protein/24 h (P < 0.05), blood pressure from 83.1 ± 1.8 to 126.6 ± 1.7 mmHg (P < 0.05), and superoxide production from 1.4 ± 0.6% to 74.3 ± 0.8% (P < 0.05). The effects of five‐sixths nephrectomy on the eNOS (?/?) mice were greater compared with wild‐type mice. Proteinuria increased from 6.7 ± 0.5 to 22.7 ± 2.0 mg protein/24 h (P < 0.05), blood pressure increased from 93.3 ± 0.9 to 151.2 ± 3.4 mmHg (P < 0.05), and superoxide production increased from 12.9 ± 0.5% to 99.8 ± 1.3% (P < 0.05). The nitrotyrosine levels were lower in eNOS (?/?) mice as compared to wild‐type mice. A combination of L‐arginine and antioxidant treatment ameliorated renal damage. The effect was improved in wild‐type animals. Conclusion Our data support the relevance of NO as an antagonist to superoxide in renal tissues and suggest that the loss of this mechanism promotes the progression of kidney failure.     

Time Course of Oxidative Stress During Open-Heart Surgery

Oxidative stress and subsequent lipid peroxidation have been suggested as pathogenetically important for postischaemic reperfusion injury. We studied the time-course of oxidative stress in 14 adults undergoing cardiac surgery, evaluating serum levels of lipid peroxidation products—diene conjugates (DC) and basal and Fe-stimulated thio-barbituric acid reactive substances (TBARS, Fe-TEBARS)—as well as markers of blood antioxidant status—serum antioxidative capacity (AOC) and red blood cell glutathione (RBC-GSH) at 6 perioperative time-points. Arterial TBARS were significantly increased 15 minutes after start of cardiopulmonary bypass, 5 minutes after release of aortic cross-clamp and 15 minutes after cessation of bypass, compared with the preoperative levels (respective means 20.8, 38.5, 34.8 vs 7.5 nmol/g protein, p < 0.05). AOC had decreased at these times (means 21.3, 18.1, 23.2 vs 34.9%, p < 0.05). The TBARS changes correlated with AOC decrease (r = 0.30, p < 0.001). Changes in serum DC and RBC-GSH were not statistically significant. All lipid peroxidation parameters had returned to preoperative levels on the following morning, while antioxidative capacity remained suppressed (28.1%, p < 0.05). These data demonstrate a definite time-course of oxidative stress markers in arterial blood during open-heart surgery.     

Polyphenolic Extract of Ichnocarpus Frutescens Attenuates Diabetic Complications in Streptozotocin-Treated Diabetic Rats

Diabetic nephropathy is one of the major complications of diabetes. Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. The aim of the study was to examine the involvement of oxidative stress in the progression of nephropathy in STZ diabetic animals and to evaluate the potential of polyphenolic extract (PPE) in the treatment of diabetes mellitus. In this study, we examined whether prolonged oral administration of polyphenolic extract of Ichnocarpus frutescens could prevent the progress or improve the outcome of diabetic nephropathy induced by oxidative stress in STZ diabetic rats. Intraperitoneal glucose tolerance test (IPGTT) revealed a significant decrease in blood glucose levels at 180 min after glucose loading in Wistar albino rats fed with PPE. During the eight weeks of experimental period, diabetic rats exhibited wide range of symptoms, including loss of body weight, hyperglycemia, polyuria, proteinuria, renal enlargement, and total renal dysfunction. A significant increase in TBARS level was observed in diabetic kidney, which was accompanied by a significant decrease in enzymatic and non-enzymatic antioxidant levels. After eight weeks, PPE-treated groups showed a lower level of blood glucose compared with non-treated STZ diabetic rats. The increases in urinary albumin and protein after eight weeks of treatment were significantly inhibited by prolonged treatment with PPE. In addition, PPE attenuates the adverse effects on hepatic biomarkers. We found that PPE can effectively protect against aldose reductase activity and protein damage (albumin glycation), and showed that its action was mainly due to enriched polyphenolic content. Our results also showed that treatment with PPE normalized the increase in hyperalgesia (i.e., the response to thermal stimuli) associated with the induction of diabetes by STZ. PPE administration in diabetic rats clearly ameliorated diabetic complications, suggesting not only a natural antioxidant but also supportive therapy for the treatment of type II diabetes.     

Effect of Hyperbaric Oxygen on Cyclosporine-Induced Nephrotoxicity and Oxidative Stress in Rats

Reactive oxygen species have been suggested to be involved in cyclosporine nephrotoxicity. Hyperbaric oxygen is known to induce the generation of reactive oxygen species in tissues. The aim of this study was to investigate whether the use of hyperbaric oxygen concurrently with cyclosporine potentiates cyclosporine nephrotoxicity by inducing oxidative stress in kidneys. The study consisted of four groups of rats: a control group, a cyclosporine group (15 mg/kg/day intraperitoneally for 14 days), a hyperbaric oxygen group (60 min. every day for five days at 2.5 atmosphere absolute), and a cyclosporine?+?hyperbaric oxygen group (cyclosporine 15 mg/kg/day intraperitoneally for 14 days?+?hyperbaric oxygen for 60 min at 2.5 atmosphere absolute every day for five days on the last five days of cyclosporine treatment). Oxidative stress was determined by measuring renal thiobarbituric acid-reactive substances content, renal superoxide dismutase, and glutathione peroxidase activities. Cyclosporine increased serum urea and creatinine levels, indicating the development of nephrotoxicity, and induced significant oxidative stress in rat kidneys. Hyperbaric oxygen alone did not alter any of the biochemical and oxidative stress parameters compared to the control group. When used concurrently with cyclosporine, hyperbaric oxygen significantly reduced cyclosporine-induced oxidative stress, but it neither attenuated nor aggravated cyclosporine-induced nephrotoxicity. These results suggest that reactive oxygen species are involved in cyclosporine nephrotoxicity, but are not the direct cause of the toxicity. Although concurrent use of cyclosporine and hyperbaric oxygen did not exacerbate cyclosporine nephrotoxicity in this model, we recommend that the renal functions of patients be monitored periodically when these treatments are used concurrently.     

Hyperoside Attenuates Hepatic Ischemia-Reperfusion Injury by Suppressing Oxidative Stress and Inhibiting Apoptosis in Rats

PurposeHepatic ischemia-reperfusion (IR) injury is a serious complication of many clinical conditions, which may lead to liver or multiple organ failure. Hyperoside, a flavonoid compound, has been reported to protect against myocardial and cerebral injury induced by IR. This study aimed to investigate the protective effects of hyperoside on hepatic IR injury in rats.MethodsUsing the 70% hepatic IR injury model, we divided 32 male Wistar rats into 4 groups (n = 8): sham-operated, IR+saline (saline/p.o.), IR+vehicle (carboxy methyl cellulose/p.o.), and IR+hyperoside (50 mg/kg/d/p.o.). At 24 hours after reperfusion, blood and liver tissue were collected. The effects of hyperoside on hepatic IR injury were assessed through tests of serum transaminase, hepatic histopathology, and measurement of markers of oxidative stress and apoptosis.ResultsPretreatment with hyperoside protected the liver from IR injury by a reduction in serum aspartate aminotransferase/alanine aminotransferase levels and a decrease in the severity of histologic changes. Hyperoside treatment also decreased the activity of malondialdehyde, increased the activities of superoxide dismutase and glutathione peroxidase, up-regulated the expression of heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1, and reduced the apoptotic index after IR injury. A decrease in the expression of caspase–3 and an increase in the ratio of B cell lymphoma 2 to B cell lymphoma 2–associated X also were observed.ConclusionHyperoside has a protective effect on hepatic IR injury in rats, which may be due to its antioxidant and antiapoptotic properties.     

Prevention of renal ischemia/reperfusion-induced injury in rats by leflunomide

OBJECTIVE: There is increasing evidence to suggest that toxic oxygen radicals play an essential role in the pathogenesis of ischemia/reperfusion (I/R) injury in the kidney. This study was designed to investigate the effects of leflunomide, an isoxazole derivative and a unique immunomodulatory agent, in I/R-induced renal injury in rats. METHODS: Forty female Sprague-Dawley rats were divided equally into four groups: (I) control (only leflunomide 10 mg/kg, intragastrically treated); (II) sham operated (only unilateral nephrectomy); (III) I/R; and (IV) leflunomide (10 mg/kg for two doses prior to experiment) plus I/R groups. In groups III and IV, after unilateral nephrectomy, the rats were subjected to 60 min of left renal pedicle occlusion, followed by 6 h of reperfusion. At the end of the reperfusion period, rats were killed and kidneys and blood were removed. Catalase, myeloperoxidase and xanthine oxidase activities, and malondialdehyde, nitric oxide and protein carbonyl levels were determined in renal tissue. Serum creatinine, blood urea nitrogen and aspartate aminotransferase were measured for the evaluation of renal function. In histopathological examination, renal damage was scored 0-3. RESULTS: Group III animals demonstrated severe deterioration of renal function, renal morphology and a significant renal oxidative stress. Pretreatment of animals with leflunomide markedly attenuated renal dysfunction, morphological alterations, reduced elevated oxidative stress products levels and restored the depleted renal antioxidant enzyme. CONCLUSION: The findings imply that oxygen radicals play a causal role in I/R-induced renal injury, and leflunomide exerts renoprotective effects probably by the radical scavenging and antioxidant activities with immunomodulatory effect.     

NADPH oxidase： recent evidence for its role in erectile dysfunction

Important roles for reactive oxygen species （ROS） in physiology and pathophysiology have been increasingly recognized. Under normal conditions, ROS serve as signaling molecules in the regulation of cellular functions. However, enhanced ROS production as a result of the activation of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase contributes significantly to the pathogeneses of vascular diseases. Although it has become evident that increased ROS is associated with erectile dysfunction （ED）, the sources of ROS in the penis remain largely unknown. In recent years, emergent evidence suggests the possible role of NADPH oxidase in inducing ED. In this review, we examine the relationship between ROS and ED in different disease models and discuss the current evidence basis for NADPH oxidase-derive＇d ROS in ED.     

Allicin Attenuates Myocardial Ischemia Reperfusion Injury in Rats by Inhibition of Inflammation and Oxidative Stress

ObjectiveTo explore the protective effect and underlying mechanism of allicin (ALC) on myocardial ischemia reperfusion (MI/R) injury in rats.MethodsThe model of MI/R injury in rats was induced by ligating the left anterior descending branch of the coronary artery. Thirty male Sprague-Dawley rats were randomly divided into 3 equal groups (n = 10): sham group, MI/R injury group, and ALC precondition group. Enzyme-linked immunosorbent assay was used to examine the expression of cardiac troponin I, CK-MB, interleukin-6, tumor necrosis factor-α, and interleukin-8 in the rats' serum. Hematoxylin and eosin staining was used to observe the myocardial pathologic morphology. A physiological recorder was used to measure cardiac systolic and diastolic function. Western blot analysis was used for detecting the expression of p38 and p-p38 in myocardium. The content of malondialdehyde and the activity of superoxide dismutase, catalase, and glutathione peroxidase in myocardium were examined by automatic analysis with the thiobarbituric acid chromogenic and dinitrobenzoic acid methods, respectively.ResultsALC can significantly decrease the expression of cardiac troponin I, CK-MB, interleukin-6, tumor necrosis factor-α, and interleukin-8 in the serum and reduce the myocardial pathologic injury and the expression of malondialdehyde and p-p38 in myocardial tissue. Moreover, ALC can upregulate the activity of superoxide dismutase, catalase, and glutathione peroxidase and improve myocardial systolic and diastolic function with no influence on the expression of p38.ConclusionALC can protect rats against MI/R injury by suppressing inflammation and oxidative stress. The mechanism is associated with alleviating the activation of p38 signaling.     

Posttreatment with Aminoguanidine Attenuates Renal Ischemia/Reperfusion Injury in Rats

Acute renal failure secondary to ischemia/reperfusion (I/R) injury is associated with significant mortality and morbidity. Aminoguanidine (AG), an inducible nitric oxide synthase inhibitor with antioxidant properties, has been reported beneficial in renal I/R injury. The aim of the present study was to investigate the effect of AG on renal I/R injury and compare the effectiveness of different AG treatment modalities. Sprague-Dawley rats were randomly assigned to one of four groups. The control group (n?=?6) received sham operation. The I/R group (n?=?6), AG-I group (n?=?8), and AG-II group (n?=?8) received bilateral renal ischemia for 45 min followed by 24 hours of reperfusion. The AG-I group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes before the induction of ischemia. The AG-II group received AG (50 mg/kg) intraperitoneally four hours and 10 minutes after the initiation of reperfusion. Serum urea and creatinine levels increased significantly in the I/R and AG-I groups compared to the control group. Kidney samples from rats in the I/R and AG-I groups revealed severe tubular damage at histopathological examination. Posttreatment with AG significantly reduced serum urea and creatinine levels and improved histopathological lesions compared with the I/R group. Although pretreatment with AG failed to protect kidneys against I/R injury in this experimental model, posttreatment with AG attenuated renal dysfunction and histopathological changes after I/R injury.     

Inhibition of geranylgeranyltransferase I decreases generation of vascular reactive oxygen species and increases vascular nitric oxide production

BACKGROUND: Vascular injury with endothelial dysfunction results in an imbalance between the production of vasoprotective molecules such as nitric oxide (NO) and deleterious reactive oxygen species (ROS). The purpose of this work was to test the hypothesis that inhibition of geranylgeranyltransferase I (GG Tase I) reduces vascular injury by increasing vascular NO production while decreasing ROS generation. METHODS AND RESULTS: GGTI-298 decreased the formation of intimal hyperplasia at 14 days following balloon injury. GGTI-298 (10 microm) inhibited activation of RhoA and Rac1 as well as inhibited SMC proliferation. GGTI increased SMC-inducible NO synthase (iNOS) levels and NO production in vitro. Additionally, the activation of NAD(P)H oxidase subunits was decreased by GGTI in vitro. This correlated with a decrease in TNF-alpha- or angiotensin-II-induced ROS production assayed by DCF fluorescence. In vivo, GGTI treatment increased endothelial NOS (eNOS) expression in uninjured arteries and iNOS expression in balloon-injured arteries. Furthermore, GGTI treatment attenuated balloon-injury-induced superoxide generation assayed by MCLA luminescence. CONCLUSIONS: GGTI decreases the production of ROS and increases the production of NO both in vitro and in vivo. These effects may be mediated via the inhibition of activation of the small GTPases Rac1 and RhoA. Pharmacological inhibition of GGTase I may prove to be a useful clinical adjunct in the treatment of cardiovascular diseases.     

Amelioration of gentamicin nephrotoxicity by green tea extract in uninephrectomized rats as a model of progressive renal failure

Rationale: Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. This study investigates whether green tea extract (GTE), an antioxidant, could ameliorate the nephrotoxic effect of GM in uninephrectomized rats. Objectives: The right kidneys of 40 rats were surgically removed and 1 week later the animals were divided into four groups (n = 10). Group 1 served as control, Group 2 as GTE group, Group 3 as GM group, and Group 4 as GM+GTE group. Kidney function, inflammatory cytokine TNF-α, oxidant and antioxidant parameters of renal tissue, as well as histopathological studies were assessed. Main findings: Injecting uninephrectomized rats with GM induced renal dysfunction as shown by significant elevations in serum creatinine and urea. Serum TNF-α and oxidative stress parameters (superoxide anion and lipid peroxides) were also significantly increased. On the contrary, antioxidative parameters [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)] were significantly decreased. Histopathological examination of renal tissue illustrated features of degeneration, marked cellular infiltration, tubular dilatation, and varying degrees of necrosis. GTE given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and TNF-α were almost normalized in the GM+GTE group. The oxidative stress parameters were significantly decreased and the antioxidative parameters were significantly increased. Conclusion: GTE ameliorates GM-induced nephrotoxicity and oxidative damage by improving antioxidant defense and tissue integrity. Further human studies are necessary to demonstrate the antioxidant effects of GTE on renal diseases. Nevertheless, green tea (GT) may offer an inexpensive, nontoxic, and effective intervention strategy in subjects with a risk for GM-induced nephrotoxicity.