A role for superoxide in gentamicin-mediated nephropathy in rats

Gentamicin is an antibiotic effective against Gram-negative infection, whose clinical use is limited by its nephrotoxicity. Oxygen free radicals are considered to be important mediators of gentamicin-mediated nephrotoxicity, but the exact nature of the radical in question is not known with certainty. We have investigated the potential role of superoxide in gentamicin-induced renal toxicity by using M40403, a low molecular weight synthetic manganese containing superoxide dismutase mimetic, which selectively removes superoxide. Administration of gentamicin at 100 mg/kg, s.c. for 5 days to rats induced a marked renal failure, characterised by a significant decrease in creatinine clearance and increased plasma creatinine levels, fractional excretion of sodium, lithium, urine gamma glutamyl transferase (gamma GT) and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was also observed in gentamicin-treated rats. M40403 (10 mg/kg, i.p. for 5 days) attenuated all these parameters of damage. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose) synthetase (PARS) activation in the proximal tubule of gentamicin-treated rats. Renal histology examination confirmed tubular necrosis. M40403 significantly prevented gentamicin-induced nitrotyrosine formation, poly(ADP-ribose) synthetase activation and tubular necrosis. These results confirm our hypothesis that superoxide anions play an important role in gentamicin-mediated nephropathy and support the possible clinical use of low molecular weight synthetic superoxide dismutase mimetics in those conditions that are associated with over production of superoxide.     

合用N-乙酰半胱氨酸和牛磺酸对实验性糖尿病大鼠的作用

目的观察合用N-乙酰半胱氨酸和牛磺酸对四氧嘧啶诱发糖尿病大鼠的作用。方法实验组灌胃给予N-乙酰半胱氨酸和牛磺酸各125mg/(d·kg),连续28d,然后测定空腹血糖浓度、血浆超氧物歧化酶(SOD)活性和全血脂质过氧化物(LPO)含量。结果合用N-乙酰半胱氨酸和牛磺酸具有明显的降血糖作用(P<0.01),并可使糖尿病大鼠全血IPO含量显著下降(P<0.01)、血浆SOD的活性明显增加(P<0.05)。结论N-乙酰半胱氨酸和牛磺酸可显著改善四氧嘧啶诱发糖尿病大鼠的糖代谢,二者合用可显示出较强的抗氧化作用。     

N-乙酰半胱氨酸对甲基苯丙胺中毒大鼠行为改变的影响

目的:探讨N-乙酰半胱氨酸(NAC)对甲基苯丙胺(METH)引起中毒大鼠模型行为改变的保护性作用机制。方法:制备大鼠中毒模型,在METH注射前30min腹腔注射NAC,应用二氯荧光乙酰乙酸盐(DCFH)作为荧光指标检测大鼠纹状体ROS的含量,以紫外分光光度计检测NOS的活性,以Sams-Dodd的方法给大鼠刻板行为评分,并计算不同组大鼠评分之间的差异。结果:NAC预处理能降低纹状体内ROS的含量(P<0.001)及NOS的活性(P<0.001),减轻METH中毒大鼠精神行为改变,降低了中毒大鼠的刻板行为评分(P<0.001)。结论:NAC可能通过逆转METH诱导大鼠纹状体区的氧化失衡状态,减轻氧化应激诱导的精神行为异常改变,产生保护性作用。     

Effect of N-acetylcysteine on colitis induced by acetic acid in rats.

(1) To verify the proposed role of reactive oxygen species (ROS) in ulcerative colitis, the effect of an antioxidant N-acetylcysteine (NAC) was studied in acetic acid (AA)-induced colonic inflammation. (2) Depending on the dose used, NAC administered intracolonically was found to reduce the extent of colonic damage, along with a decrease in myeloperoxidase (MPO) activity, colonic wet weight and wet/dry weight ratio. (3) NAC attenuated the enhanced vascular permeability and prevented the depletion of colonic reduced glutathione (GSH) caused by AA administration. (4) The findings indicate that NAC may prove beneficial in the treatment of colitis.     

大黄酸对大鼠慢性移植肾肾病的影响

目的 探讨大黄酸对大鼠慢性移植肾肾病(CAN)模型移植肾的治疗作用.方法 建立30只大鼠CAN模型,分成模型对照组(A组)16只,大黄酸治疗组(B组)14只.于移植后1、2、4个月分别收集大鼠的血和尿样,检测肾功能及尿蛋白含量.并于移植后2、4个月宰杀大鼠,观察A、B组大鼠移植肾组织病理学变化,并检测肾结缔组织生长因子(CTGF)的表达.结果 与A组比较,B组大鼠肾功能明显改善,肾组织病理检查示肾间质纤维化及间质炎症明显减轻,肾组织CTGF表达降低(P＜0.05).结论 大黄酸可通过降低CTGF表达改善CAN大鼠肾功能及肾脏慢性病变.     

N-乙酰半胱氨酸和L-NAME对磷化铝诱导的大鼠心血管毒性的作用(英文)

AIM: To investigate the protective effects of N-acetyl-cysteine (NAC) and N~ω-Nitro-L-arginine methyl ester(L-NAME) on aluminium phosphide (AlP) poisoninginduced hemodynamic changes, myocardial oxygen freeradical in injury and on survival time in rats. METH-ODS: AlP (12.5 mg/kg) was administered intragastri-cally under urethane anaesthesia. The effect of pre- andpost-treatment with NAC and L-NAME alone and incombination was studied on haemodynarnic parameters[blood pressure (BP), heart rate (HR), and electrocar-diogram (ECG) ] and biochemical parameters (malonyl-     

Effect of N-acetylcysteine on plasma adiponectin and renal adiponectin receptors in streptozotocin-induced diabetic rats

This study investigated the effect of N-acetylcysteine on plasma adiponectin, renal adiponectin receptors, lipid metabolism and oxidative stress in streptozotocin-induced diabetic rats. Metabolic parameters, plasma adiponectin level, renal protein expression of adiponectin receptors were analyzed in controls and diabetic rats treated with or without N-acetylcysteine in drinking water for 8 weeks. Plasma lipid, creatinine and free 5-F(2t)-isoprostane levels, urine protein excretion rate, mesangial matrix expansion index, and protein expression of renal connective tissue growth factor (CTGF) were increased in diabetic rats. The decreased plasma adiponectin levels and renal protein expression of adiponectin receptor 1 were accompanied by the decreased renal phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK)-alpha (Thr172) and protein expression of phospho-acetyl coenzyme A carboxylase (ACC) (Ser79) which led to the increased renal triglyceride levels in diabetic rats. There was no difference in the protein expression of renal adiponectin receptor 2 between control and diabetic rats. N-acetylcysteine treatment attenuated the increased oxidative stress, plasma and renal lipids, urine protein excretion rate, mesangial matrix expansion index, and protein expression of renal CTGF, but did not affect plasma adiponectin levels, renal protein expression of adiponectin receptor 1, phosphorylation of AMPK-alpha (Thr172) and renal protein expression of phospho-ACC (Ser79) in diabetic rats. These results suggested that the decreased plasma adiponectin and renal adiponectin receptor 1 result in the increased renal triglyceride that stimulates renal CTGF expression leading to the renal hypertrophy and the deteriorated renal function in the diabetic rats. N-acetylcysteine treatment attenuates the increased oxidative stress, but has no effect on the decreased plasma adiponectin and renal adiponectin receptor 1 in diabetic rats, indicating that oxidative stress may not contribute to the decreased plasma adiponectin and renal adiponectin receptor 1 protein expression in diabetic rats.     

Effect of edaravone in diabetes mellitus-induced nephropathy in rats

Edaravone, a synthetic-free radical scavenger, has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine and renal vascular resistance. The present study investigated the effect of edaravone in diabetes mellitus-induced nephropathy in rats. A single administration of streptozotocin (STZ, 55 mg/kg, i.p.) was employed to induce diabetes mellitus in rats. The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy. Mean body weight, lipid alteration, renal functional and histopathology were analysed. Diabetic rats developed nephropathy as evidenced by a significant increase in serum creatinine and urea, and marked renal histopathological abnormalities like glomerulosclerosis and tubular cell degeneration. The kidney weight to body weight ratio was increased. Moreover, diabetic rats showed lipid alteration as evidenced by a signifi cant increase in serum triglycerides and decrease in serum high-density lipoproteins. Edaravone (10 mg/kg, i.p., last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum creatinine and urea and preventing renal structural abnormalities. In addition, its treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum high-density lipoproteins. Interestingly, the renoprotective effect of edaravone was comparable to that of lisinopril (5 mg/kg, p.o, 4 weeks, standard drug). Edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus. Edaravone has a potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct renoprotection in diabetic rats.     

乙酰半胱氨酸对不同病程糖尿病大鼠心肌缺血再灌注后心功能的影响

目的：观察乙酰半胱氨酸（NAC）对不同病程糖尿病（DM）大鼠心肌缺血再灌注（I/R）后心功能的影响.方法：72只糖尿病大鼠随机分为假手术组（Ds组,n=24）、I/R组（Dr/R组,n=24）和I/R＋NAC治疗组（DN组,n=24）.每组再随机分为2组（n=12）,分别在2周（DS2、DI/R2和DN2）和8周（DS8、DI/R8和DN8）时进行实验.记录左心室发展压（LVDP）、收缩期和舒张期左心室内压的最大变化速率（±dp/dtmax）,检测肌酸激酶同工酶（CK-MB）活性和丙二醛（MDA）含量.结果：（1）基础状态下,DS8和DI/R8组大鼠各项心功能参数低于对应的DS2和DI/R2组（P＜0.05）.DN8组心功能参数高于DI/R8组,但低于DN2组（P＜0.05）.（2）缺血/再灌注后,DI/R8组LVDP和±dp/dtmax%的恢复百分率低于DI/R2组和DN8组（P＜0.01）,CK-MB和MDA高于DI/R2组和DN8组（P＜0.01）;DN8组心功能参数恢复百分率低于DN2组（P＜0.01）.结论：8周DM鼠基础心功能低于2周DM鼠,I/R后心功能受损程度比2周DM鼠严重,补充NAC可改善8周DM鼠基础心功能,但防治I/R损伤效果不如2周DM鼠.     

N-乙酰-L-半胱氨酸减轻大鼠糖尿病肾病的机制探讨

目的研究N-乙酰-L-半胱氨酸(NAC)减轻大鼠糖尿病肾病(DN)的机制。方法 30只清洁级雄性SD大鼠随机分为健康对照组(Sham组)、糖尿病肾病组(DN组)、NAC组,各组分别给予不同的干预。动物取肾后测定肾皮质中丙二醛(MDA)含量,超氧化物歧化酶(SOD)活性,采用反转录-聚合酶链反应(RT-PCR)法检测各组大鼠肾皮质中Caspase-3的mRNA表达。结果 NAC能降低DN大鼠肾皮质中MDA含量,使SOD活性增强,凋亡相关因子Caspase-3的mRNA表达减少。结论 NAC保护大鼠DN的机制是通过抑制氧化应激、减少肾皮质细胞凋亡而实现的。     

Effect of licorice extract on the complications of diabetes nephropathy in rats

The aim of this study was to investigate the protective action of licorice in diabetic nephropathy in male rats. Diabetes was induced in male Wistar rats by using streptozotocin (60 mg/kg body weight). Daily oral ingestion (1 g/kg body weight) of licorice extract for 60 days after the onset of diabetes reversed the adverse effect of diabetes on rats. Licorice extract alleviated blood glucose levels, restored renal function, and attenuated body-weight loss. In addition, licorice extract modulated the adverse effect of diabetes on renal malondialdehyde, glutathione, superoxide dismutase, and catalase activity. Further, licorice extract restored the total antioxidant capacity of diabetic rat kidneys. The biochemical analyses were reinforced by histologic investigations, where focal segmental glomerulosclerosis, tubular damage, and hyperemic kidney were the histologic changes seen in diabetic, but not in treated, rats. In conclusion, the biochemical analysis and the histologic investigations of diabetic rat kidneys treated with licorice extract revealed that licorice may have a potential therapeutic effect for diabetes due to its antioxidant and -hyperglycemic properties.     

Effect of licorice extract on the complications of diabetes nephropathy in rats

The aim of this study was to investigate the protective action of licorice in diabetic nephropathy in male rats. Diabetes was induced in male Wistar rats by using streptozotocin (60?mg/kg body weight). Daily oral ingestion (1?g/kg body weight) of licorice extract for 60 days after the onset of diabetes reversed the adverse effect of diabetes on rats. Licorice extract alleviated blood glucose levels, restored renal function, and attenuated body-weight loss. In addition, licorice extract modulated the adverse effect of diabetes on renal malondialdehyde, glutathione, superoxide dismutase, and catalase activity. Further, licorice extract restored the total antioxidant capacity of diabetic rat kidneys. The biochemical analyses were reinforced by histologic investigations, where focal segmental glomerulosclerosis, tubular damage, and hyperemic kidney were the histologic changes seen in diabetic, but not in treated, rats. In conclusion, the biochemical analysis and the histologic investigations of diabetic rat kidneys treated with licorice extract revealed that licorice may have a potential therapeutic effect for diabetes due to its antioxidant and -hyperglycemic properties.     

Preventive effect of N-acetylcysteine on contrast-induced nephropathy following coronary angiography and angioplasty

Contrast-induced nephropathy (CIN) is one of the serious side effects of contrast media. A few studies have suggested that N-acetylcysteine (NAC) is effective to prevent CIN, but the efficacy remains unclear in Japanese. Therefore, we retrospectively studied the preventive effect of NAC on CIN in Sakakibara Heart Institute. Patients who had been administered NAC for the purpose of preventing CIN before coronary intervention between February 2005 and November 2006 were included in the NAC group. In addition, age- and rate of diabetes mellitus-matched controls were randomly extracted. We retrieved and analyzed patient data including demographics, NAC dosage, and serum creatinine concentrations (Scr). NAC group (n=16) showed significantly higher baseline Scr (p<0.01) and a tendency toward a lower dose of contrast media (p=0.068) compared with controls (n=48). Since the occurrence of CIN was low, there was no significant difference in the proportion of CIN between the groups (NAC: 6%, controls: 4%). NAC group trended toward a decrease in Scr after the use of contrast media, while controls increased (-0.04+/-0.25 versus +0.03+/-0.36 mg/dl, p=0.096). The multivariate analysis showed that the dosage of NAC is inversely correlated with Scr independent of baseline Scr and dosage of contrast media. Despite higher baseline Scr (i.e., high-risk with CIN) in the NAC group, the real Scr value reflected a lower trend on average. In addition, this finding suggests that a larger dose of NAC results in a lower Scr value, we consider that the NAC dosage more likely prevented CIN.     

Effect of mononuclear cells versus pioglitazone on streptozotocin-induced diabetic nephropathy in rats

BackgroundDiabetic nephropathy is a serious diabetic complication that leads to end stage renal disease. Cell therapies with human embryonic and specific adult stem cells have emerged as an alternative management for various diseases.MethodsTo test this hypothesis, the present study was conducted to compare effect of MNCs treatment (iv injection once in the tail vein for diabetic rats in a dose of 150 × 10⁶ MNCs cells/rat) versus pioglitazone (10 mg/kg, for eight weeks) on improving the renal structure and function changes and reducing laminin deposition associated with STZ-induced diabetic nephropathy in rats.ResultsTreatment with pioglitazone or MNCs, demonstrated a significant improvement in the STZ-induced renal functional and structural changes in comparison with diabetic control group. Additionally, our histopathological and immunohistochemical studies confirm these results. Meanwhile, MNCs treated group exhibited more improvement in all studied parameters as compared to pioglitazone treated group.ConclusionThese data indicate that MNCs treatment was superior to pioglitazone in controlling hyperglycemia, improving the renal structure and function changes and reducing renal laminin expression associated with STZ-induced diabetic nephropathy in rats.     

Influence of N-acetylcysteine on the hexachlorobenzene induced porphyria in rats

The course of hexachlorobenzene (HCB) induced porphyria was not influenced by the concomitant administration of N-acetylcysteine (NAC) to the animals: urinary excretion of total porphyrins and porphyrin precursors as well as the hepatic aminolevulinate synthase activities were not influenced by NAC treatment. In addition, no differences could be shown between the HCB and the HCB/NAC combination group concerning the hepatic cytochrome P-450 contents or the P-450 dependent enzyme activities.     

N-乙酰半胱氨酸对经皮冠状动脉介入术后发生造影剂肾病的预防作用研究

目的探讨N-乙酰半胱氨酸(NAC)对经皮冠状动脉介入治疗(PCI)术后发生造影剂肾病(CIN)的预防作用。方法选择2010年3月至2012年4月在阳江市人民医院心内科住院拟行PCI的240例患者,按1∶1比例分为NAC组及安慰剂组。NAC组:患者于术前及术后12 h服用NAC 1 200 mg 1次;安慰剂组:于术前、术后服用与NAC颜色及味道相似的安慰剂。CIN定义为:冠状动脉造影术后48~72 h内血清肌酐值较基线绝对值升高,大于或等于0.5 mg/dL(44.2μmol/L)或25%。结果 240例患者中,29例发生CIN,总发生率达12.1%,NAC组15例(12.5%),安慰剂组14例(11.7%),两组比较,差异无统计学意义(χ2=14.65,P=0.78)。30 d内复合终点事件(如死亡或需要透析)发生率:NAC组为2.2%,安慰剂组为2.3%,两组比较,差异无统计学意义(P=0.92)。结论 NAC在预防CIN发生方面并无显著优势,同时,NAC并不能减少患者30 d内主要心血管不良事件的发生。     

Effects of N-acetylcysteine on methotrexate-induced small intestinal damage in rats

Methotrexate (MTX) is known to cause damage to the small intestine, leading to its dysfunction. The aim of the present study was to examine whether the administration of N-acetylcysteine (NAC) provides protection against the MTX-induced damage to small intestinal epithelium in rats. A single dose of MTX (20 mg/kg, intraperitoneal) was followed by intraperitoneal saline or NAC administration (150 mg/kg, MTX+NAC group) for the next 5 days. Afterward, the rats were sacrificed and small intestinal segments were fixed for light microscopic examinations. Glutathione and malondialdehyde levels, myeloperoxidase, superoxide dismutase and catalase activities were measured in the other intestinal segments. MTX caused an increase in the levels of glutathione and malondialdehyde and in the activities of myeloperoxidase, superoxide dismutase and catalase. These changes were significantly reversed in MTX+NAC-treated rats. Light microscopy in the MTX group revealed mucosal damage, which decreased with NAC treatment. Our results confirmed that administration of NAC decreased the MTX-induced damage to the small intestine. This protective effect of NAC may have clinical applications in chemotherapy.     

N-乙酰半胱氨酸对肝缺血再灌注损伤大鼠Toll样受体4表达的影响

目的：探讨N-乙酰半胱氨酸(N-acetylcysteine,NAC)对肝缺血再灌注(ischemic reperfusion,I/R)损伤大鼠Toll样受体4(Toll-like receptor 4,TLR4)表达的影响。方法：Wistar大鼠随机分为3组：假手术组(P)、I/R组、I/R+NAC组。P组只开腹不阻断肝血流,另2组阻断大部肝血流后再灌注,其中I/R+NAC组再灌注前5 min尾静脉给予300 mg/kg NAC。各组分别检测不同时间点的血丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、脂多糖(LPS)与肝组织TLR4 mRNA及其蛋白。结果：在各时间点,P组血ALT,AST,LPS和肝绍织TLR4表达无显著差异；另2组较P组均有显著升高,但I/R+NAC组各指标升高低于I/R组。肝组织TLR4 mRNA表达在I/R组从3 h起显著增强并维持高表达,而I/R+NAC组各时相无显著变化；但两者TLR4蛋白表达变化类似,都在6,24 h表达显著增强。结论：LPS及其TLR4参与了I/R肝损伤的病理过程；NAC减弱肠源性LPS及其启动的TLR4炎症信号通路而保护缺血再灌注肝损伤。     

益气养肾方对糖尿病肾病大鼠氧化应激的影响观察

目的：观察益气养肾方对糖尿病肾病大鼠应激反应水平的影响。方法选择10周龄SD大鼠50只,选取其中10只作为对照组,给予常规低脂、低糖饮食。其余40只采用高脂、高糖喂养联合低剂量（30mg/kg）链脲佐菌素诱导糖尿病肾病大鼠动物模型。建模成功后随机分为模型组与观察组各20只。观察组在模型组饮食基础上将药物益气养肾方按人与大鼠体表面积折算动物等效药量,按生药20g·kg-1·d-1,灌胃,连续灌胃3周。模型组同期继续给予高脂、高糖饮食。3周后杀死大鼠,手术摘取肾脏。病理切片观察3组肾脏组织形态学变化,比较3组大鼠肾脏肥大指数（ kW/BW）、尿蛋白排泄量（24hUP）、血肌酐（ Scr）水平、肾皮质丙二醛（ MDA）含量、肾皮质超氧化物歧化酶（SOD）活性、肾皮质谷胱甘肽过氧化物酶（GSH-Px）。结果3组大鼠光镜下观察：对照组大鼠肾小球及肾小管正常,基底膜及系膜区结构清楚。模型组大鼠HE染色见肾小球肥大,肾小球毛细血管基底膜不规则增厚,肾小管上皮细胞肥大,内有糖原沉积表现,肾小管间纤维变性。观察组光镜观察可见与模型组相似病理改变,但肾小球肥大及肾小管肿胀较轻,蛋白管型较少。模型组及观察组kW/BW、24hUP、Scr较对照组明显升高,差异均有统计学意义（P＜0.05）,但观察组kW/BW、24hUP、Scr较模型组明显减少,差异均有统计学意义（ P＜0.05）。模型组及观察组MDA含量明显升高,SOD及GSH-Px较对照组明显降低,差异均有统计学意义（ P＜0.05）。观察组MDA含量较模型组明显减少,SOD、GSH-Px较模型组明显增加,差异均有统计学意义（ P＜0.05）。结论益气养肾方可能通过抑制糖尿病肾病大鼠体内氧化应激反应来减轻肾脏损伤,改善糖尿病肾病大鼠肾脏结构及起到功能保护作用。     

N-乙酰半胱氨酸对硫代乙酰胺致大鼠肝衰竭的防治作用

目的：观察Ｎ－乙酰半胱氨酸（Ｎ－ａｃｅｔｙｌｃｙｓｔｅｉｎｅ,ＮＡＣ）对硫代乙酰胺（Ｔｈｉｏａｃｅｔａｍｉｄｅ,ＴＡＡ）引起大鼠暴发性肝衰竭（Ｆｕｌｍｉｎａｎｔ Ｈｅｐａｔｉｃ Ｆａｉｌｕｒｅ,ＦＨＦ）的预防治疗作用。方法：取ＳＤ♂大鼠分６组,除正常对照组外,均ｉｐ ＴＡＡ３００ｍｇ／ｋｇ,给药组同时ｉｐＮＡＣ２４ｈ后取血及肝脏,进行血清生化、血浆一氧化氮（Ｎｉｔｒｉｃ ｏｘｉｄｅ,ＮＯ）、肝脏还