Treatment of hyperlipidemia with probucol suppresses the development of focal and segmental glomerulosclerosis in chronic aminonucleoside nephrosis.

We have recently reported that a lipid-lowering agent, probucol, reduces proteinuria in puromycin aminonucleoside (PA)-induced nephrotic rats (PAN). In this study, we examined whether a long-term treatment of hyperlipidemia with probucol can suppress the development of focal and segmental glomerulosclerosis (FSGS) in chronic PAN. A chronic PAN model was made with repeated intraperitoneal injections of PA (initially 100 mg/kg body weight followed by 25 mg/kg 5 times at 2-week intervals). Two weeks after the first injection of PA, either normal rat chow with or without 1% probucol was given to the nephrotic rats for 10 weeks. Chronic PAN exhibited remarkable proteinuria, hypoalbuminemia and severe hyperlipidemia with all lipoprotein fractions increased. Probucol treatment significantly reduced the lipid concentration in all major lipoproteins, significantly reduced proteinuria and increased plasma albumin concentration. Plasma albumin inversely correlated with cholesterol or phospholipid in low-density and high-density lipoproteins, suggesting that the lipid-lowering effect of probucol may ameliorate the hypoalbuminemia associated with nephrosis. In light microscopic examination, various degrees of FSGS with tubulointerstitial lesions were observed in the renal cortex from chronic PAN. The degree of FSGS was scored from grades 1 to 4 according to severity. One half of the untreated PAN (4/8) was classified into grade 4 and the other into grades 2 or 3, whilst one half of treated PAN (4/8) was classified either into grade 1 or 2. The grading of FSGS correlated negatively with plasma albumin concentration. These results demonstrate that probucol is highly effective upon nephrotic hyperlipidemia and suggest that a long-term treatment of secondary hyperlipidemia can suppress progressive renal injury associated with chronic nephrosis.     

普罗布考防治大鼠顺铂急性肾损伤的实验研究

目的：复制大鼠顺铂急性肾损伤模型,研究氧化应激与核转录因子Sp1及凋亡的关系;探讨普罗布考对顺铂急性肾损伤的保护作用及作用机制。方法：24只SD雄性大鼠被随机分为生理盐水对照组、顺铂模型组、普罗布考干预组、普罗布考对照组,每组6只;检测尿N-乙酰-β-D-氨基葡萄糖甘酶（NAG）、血清肌酐（Scr）、血尿素氮（BUN）、肾组织匀浆液丙二醛（MDA）和谷胱甘肽过氧化物酶（GSH-Px）,光镜观察肾脏病理改变;采用免疫组化染色检测肾组织Sp1蛋白表达;采用TUNEL染色检测肾小管上皮细胞凋亡。结果：与生理盐水对照组和普罗布考对照组相比,顺铂模型组大鼠血清BUN和Scr,尿NAG酶,肾脏组织匀浆MDA含量显著升高,肾组织匀浆GSH-Px活力显著下降（P〈0.01）;肾脏指数、肾小管损伤分数和肾小管上皮细胞凋亡百分比均明显增加（P〈0.01）;肾组织Sp1蛋白的表达上调。采用普罗布考干预后血清BUN和Scr,尿NAG酶,肾脏组织匀浆MDA含量显著下降（P〈0.05）;肾组织匀浆GSH-Px活力显著升高;肾脏指数、肾小管损伤分数和肾小管上皮细胞凋亡百分比均明显降低（P〈0.01）;肾组织Sp1蛋白的表达下调。结论：氧化应激和核转录因子Sp1在顺铂所致大鼠肾毒性中起一定作用;普罗布考对顺铂所致大鼠肾毒性有保护作用,其机制可能与抗氧化、抑制肾小管上皮细胞凋亡、下调肾组织Sp1蛋白表达有关。     

Role of the 5-lipooxygenase pathway in obstructive nephropathy.

Leukotrienes are products of the 5-lipooxygenase pathway of arachidonic acid metabolism that possess potent inflammatory properties. We examined the potential role of this pathway in the decrease in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) observed in rats after unilateral release of bilateral ureteral obstruction (BUO) of 24 hours duration. Isolated glomeruli from rats with BUO produced significantly greater amounts of leukotriene B4 (LTB4) than glomeruli from sham-operated rats (SOR; P less than 0.0001). Glomeruli from rats with BUO given MK886, an inhibitor of the 5-lipooxygenase enzyme, or from rats with BUO subjected to both total body irradiation to prevent the leukocyte infiltration of the kidney and also given MK886 prior to obstruction, produced amounts of LTB4 not significantly different from those in glomeruli of SOR. Glomeruli from rats with BUO that had only total body irradiation prior to obstruction produced significantly less LTB4 than glomeruli from untreated BUO rats, but LTB4 production was still significantly greater than in glomeruli from SOR. There were no significant differences in GFR among SOR, SOR given MK886, and SOR subjected to total body irradiation. However, SOR given MK886 had significantly higher ERPF and lower renal vascular resistance (RVR) than SOR not pretreated with the lipooxygenase inhibitor. Rats with BUO given MK886, or subjected to total body irradiation, or both, prior to obstruction had significantly greater GFR and ERPF values and lower RVR than untreated BUO rats. Glomeruli from rats with BUO which were not pretreated had three times the leukocytes of glomeruli from SOR. This leukocyte infiltrate was composed of macrophages (about 55%) and neutrophils (about 45%).(ABSTRACT TRUNCATED AT 250 WORDS)     

The lowering effect of probucol on plasma lipoprotein and proteinuria in puromycin aminonucleoside-induced nephrotic rats

Hyperlipidemia associated with nephrotic syndrome was treated with probucol and the changes in plasma lipoprotein lipid concentration and urinary protein excretion were examined in puromycin aminonucleoside-induced nephrotic rats. Rats made nephrotic exhibited severe hyperlipidemia with increases in all major lipoprotein fractions. Probucol treatment of nephrotic rats significantly lowered plasma triglyceride (TG), cholesterol (Ch) phospholipid (PL) and apoprotein B associated with very-low-density and low-density lipoprotein and Ch and PL in high-density lipoprotein (HDL). Malondialdehyde (MDA) associated with the lipoproteins was significantly elevated in nephrotic rats and probucol treatment also lowered MDA concentration in all major lipoproteins. In control rats probucol moderately, but significantly, reduced plasma TG and HDL-Ch concentrations. Proteinuria associated with nephrosis was decreased significantly by treatment with probucol. Probucol treatment did not affect blood urea nitrogen and plasma creatinine levels. A significant positive correlation existed between the amount of protein excreted in urine and the plasma lipid concentrations in all nephrotic rats, suggesting that the hypolipidemic effect of probucol may attenuate proteinuria associated with nephrosis. These results suggest that probucol may be a favorable treatment for hyperlipidemia associated with nephrotic syndrome.     

Reactive oxygen metabolites in endotoxin-induced acute renal failure in rats

Based on recent reports that reactive oxygen metabolites may play a role in endotoxin-induced injury in other tissues, we postulated that reactive oxygen metabolites may be important mediators of endotoxin-induced acute renal failure. Superoxide dismutase, a scavenger of superoxide, or catalase, which destroys hydrogen peroxide, did not protect against endotoxin-induced renal failure. Similarly, neither the hydroxyl radical scavenger dimethylthiourea nor the iron chelator deferoxamine (which presumably would act by preventing the generation of hydroxyl radical via the iron-catalyzed Haber-Weiss reaction) prevented the endotoxin-induced fall in renal function. In separate experiments, we found no increase in renal cortical lipid peroxidation (a marker of reactive oxygen metabolite-mediated tissue injury) in endotoxin-treated rats, providing further evidence against a role for reactive oxygen metabolites in endotoxin-induced renal injury. Finally, using the aminotriazole-induced inhibition of catalase (a measure of in vivo changes in the hydrogen peroxide generation) we found no evidence of enhanced hydrogen peroxide generation in the renal cortex in endotoxin-treated rats. Taken together, the data from these three separate experimental approaches suggest that reactive oxygen metabolites are not important mediators of endotoxin-induced acute renal failure.     

Effect of leukocyte depletion on the function of the postobstructed kidney in the rat

We have observed an influx of leukocytes, predominantly macrophages, into the cortex and medulla of the kidney following ureteral obstruction. To examine the potential contribution of these infiltrating cells to the decrease in GFR and RPF that occurs following ureteral obstruction, 16 male Lewis rats (wt 246.4 +/- 4.0 g) were studied in the awake state three hours after unilateral release of 24 hours of bilateral ureteral obstruction (BUO). Eight rats were not irradiated, and eight rats received 1315 rads one day prior to the obstruction. The leukocyte infiltrate following 24 hours of ureteral obstruction was quantified with and without prior irradiation in an additional eight rats. Irradiation reduced cortical infiltration (27.05 +/- 3.07 x 10(5) vs. 1.2 +/- 0.83 x 10(5) cells/g tissue) and medullary infiltration (13.6 +/- 1.79 x 10(5) vs. 0.86 +/- 0.45 x 10(5) cells/g tissue) of leukocytes following BUO (P less than 0.001 for both) and increased postobstruction GFR (1.58 +/- 0.12 vs. 2.97 +/- 0.15 ml/min/kg body wt, P less than 0.001). Eleven rats, six of which received irradiation, underwent sham laparotomy without BUO in order to assess the effect of irradiation alone on renal function. Irradiation had no effect on the renal function of non-obstructed rats. Urinary excretion of thromboxane B2 increased following BUO and this rise was significantly blunted by irradiation prior to BUO (9.53 +/- 2.14 vs. 32.46 +/- 4.95 vs. 19.03 +/- 1.94 pg/min). Fractional excretion of sodium and water was reduced by irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of G Proteins in Obstructed Kidneys

Background: Urinary tract obstruction has a marked effect on renal function. Activation of phospholipases which results in incremental production of vasoactive eicosanoids may contribute to the hemodynamic changes characteristic of an obstructed kidney. G proteins play an important role in transmembrane signal transduction, which controls phospholipase activities and eicosanoid production. The present study was designed to determine the presence of G proteins in obstructed kidneys in rats, and to characterize the differences between unilateral ureteral obstruction (UUO) and bilateral ureteral obstruction (BUO).
Methods: Several G-protein α subunits (Gas, Gαi1,2, and Gαi3) and the β subunit (Gβ) were determined by immunoblotting and immunocytochemical techniques using specific antibodies against these G proteins.
Results: lmmunoblots demonstrated a decreased Gαi3 content in the outer medullary tubules and a significantly lower Gβ level in the glomeruli of UUO. In BUO, there was an increased leeel of Gβ in the cortical tubules, and the Gαs level was markedly reduced in the inner medullary tubules.
Immunocytochemical studies revealed that these G proteins were predominantly localized in the brush border side of the cortical tubules. However, we could not demonstrate staining differences between UUO and BUO.
Conclusions: These results indicate that a modulation of G-protein-coupled transmembrane signal transduction may contribute to the renal functional changes in an obstructed kidney. A different level of expression of G-protein subunits between UUO and BUO may be a factor in the differences of hemodynamics and renal tubular damage between UUO and BUO.     

Immunological aspects of acute ureteral obstruction: immune cell infiltrate in the kidney

Kidneys from rats subjected to bilateral ureteral obstruction (BUO), unilateral ureteral obstruction (UUO) and UUO with subsequent release were analyzed for leukocyte infiltration. A time-dependent influx of leukocytes, predominantly macrophages and suppressor T lymphocytes, occurred in both the cortex and medulla following obstruction, and disappeared with release of the obstruction. Glomerular macrophages declined following obstruction but increased to levels above control following release. The influx of leukocytes following obstruction was paralleled by an increase in thromboxane B2 excretion by the kidney and coincided with a decrease in glomerular filtration rate (GFR). This would suggest that an influx of immune cells is a prominent feature of the acute renal response to ureteral obstruction. These cells may modulate some of the post-obstructive alterations in renal function via the production of vasoactive substances, such as thromboxane A2.     

Differential effects of probucol on two distinct experimental rat nephrosis models

We compared an antiproteinuric effect of a lipid‐lowering agent probucol on two distinct types of experimental nephrosis in rats, i.e. mercuric–chloride (HgCl₂)‐induced autoimmune glomerulonephritis in Brown Norway (BN) rats and puromycin aminonucleoside (PA)‐nephrosis in Wistar rats. The rats were fed either standard rat chow or chow containing 5% probucol. BN rats were treated with HgCl₂ according to a standard protocol (HgCl₂ 1 mg/kg subcutaneously three times/week). Probucol treatment did not ameliorate proteinuria, renal histology or a strong linear staining for IgG and an intercellular adhesion molecule, ICAM‐1, in glomeruli. Wistar rats were made nephrotic with an intraperitoneal injection of PA (100 mg/kg). In this model, in contrast to the BN rat model, no glomerular deposition of IgG or ICAM‐1 was observed. Probucol treatment ameliorated proteinuria significantly. These findings suggest that the response to probucol differs in different experimental nephrosis models. As probucol only affects PA‐nephrosis, in which ICAM‐1 expression is negative, the ICAM‐1 attenuation is not likely to be involved in the antiproteinuric effect of probucol.     

EDRF role in renal function and blood pressure of normal rats and rats with obstructive uropathy.

There is a decrease in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) and an increase in mean arterial pressure (MAP) and renal vascular resistance (RVR) after release of bilateral ureteral obstruction (BUO) of 24 hours duration. The present studies examine the role of endothelium-derived relaxing factor (EDRF) in the renal hemodynamics of sham-operated rats (SOR) and rats in which BUO of 24 hours duration was unilaterally released. In both groups of rats, renal function and blood pressure were measured in the awake state under basal conditions and after administration of L-arginine (L-arg), the substrate for EDRF synthesis, followed by NwNAME, an L-arg antagonist, or after administration of NwNAME followed by L-arg. Administration of L-arg alone to SOR did not affect renal function, MAP or RVR. In SOR given L-arg and then NwNAME, there was significantly decreased GFR and ERPF and increased MAP and RVR. When NwNAME was given initially, similar changes were obtained, and these were reversed by the administration of L-arg. Rats given L-arginine immediately after unilateral release of BUO of 24 hours duration had significantly greater GFR and ERPF values and lower MAP and RVR than temporal controls. NwNAME given to BUO rats decreased renal function further and increased MAP and RVR. We found a dose-dependent increase in GFR and ERPF and a dose-dependent decrease in MAP and RVR in both SOR and rats with BUO given increasing amounts of L-arg. There was also a dose-dependent decrease in GFR and ERPF and an increase in MAP and RVR in SOR and rats with BUO given increasing amounts of NwNAME or NGNMA, the two different antagonists of L-arg. In another set of experiments, SOR and rats with BUO were given L-arg preoperatively (that is, 24 hr prior to study). Both groups of rats had significantly higher GFR and ERPF values and lower MAP and RVR than control rats. Sham-operated rats given NwNAME 24 hours prior to study had significantly lower GFR and ERPF and higher MAP and RVR than untreated rats. Rats with BUO given NwNAME prior to obstruction had no measurable renal function and had significantly higher values for MAP after release of obstruction. These studies confirm the role of L-arg administration, and presumably EDRF, in the regulation of MAP and renal function in sham-operated rats. The results of this study also suggest decreased availability of arginine for EDRF synthesis in rats with BUO.(ABSTRACT TRUNCATED AT 400 WORDS)     

Age-dependent renal expression of acid-base transporters in neonatal ureter obstruction

Congenital obstructive nephropathy accounts for a major proportion of renal insufficiency in infancy and childhood. In an earlier investigation we demonstrated that bilateral complete ureteral obstruction (BUO) in rats is associated with inadequate urinary acidification [Am J Physiol Renal Physiol. 295(2):F497-506, 2008]. The aim of the study reported here was to determine whether this defect is also associated with unilateral ureteral obstruction (UUO), which is clinically more common than BUO. The time-course of the changes in protein expression levels of major renal acid–base transporters was examined at 7 and 14 weeks in rats with neonatally induced partial unilateral ureteral obstruction (PUUO), which was performed within the first 48 h of life. We observed that protein expression of the renal acid–base transporters NHE3, NBC1, NBCn1, pendrin and Na⁺-K⁺-ATPase was increased in both obstructed and non-obstructed kidneys 7 weeks after the induction of neonatal PUUO. This was confirmed by immunocytochemistry. In contrast, 14 weeks after the induction of PUUO, there was a significant downregulation of the renal acid–base transporters NBC1, NBCn1 and Na⁺-K⁺-ATPase in the obstructed kidneys. These time/age-dependent changes in protein expression were associated with parallel changes in renal function resulting in urine acidification in response to exogenous acid loading. In conclusion, these results show that downregulation of protein expression is a time/age-dependent response to PUUO, which could contribute to the decreased net acid excretion and development of metabolic acidosis in neonatal rats with PUUO.     

Renal function after release of ureteral obstruction: role of endothelin and the renal artery endothelium.

Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) are decreased and mean arterial pressure (MAP) is increased after unilateral release of bilateral ureteral obstruction (BUO). An imbalance between vasoconstrictor and vasodilator substances may explain the hemodynamic alterations seen in this setting. The present study examines the role of endothelin-1 in such alterations. Rats with BUO (N = 10) had significantly lower GFR and ERPF (ml/min/kg body wt) than sham-operated rats (SOR, N = 9) (1.40 +/- 0.14 vs. 6.20 +/- 0.38 and 5.12 +/- 0.68 vs. 20.2 +/- 2.20, respectively) and significantly higher MAP (mm Hg) than SOR (154.9 +/- 3.2 vs. 120.6 +/- 1.7). Rats with BUO given a specific antiendothelin antibody (N = 8) had significantly higher GFR (2.10 +/- 0.12) and ERPF (7.46 +/- 0.95) than BUO control rats, but there were no significant changes in MAP (159.5 +/- 5.8). In SOR (N = 6), mechanical denudation of the main renal artery endothelium did not significantly affect renal function when compared to renal function in control SOR. However, the same maneuver significantly lowered GFR (0.64 +/- 0.17) and ERPF (1.67 +/- 0.36) in BUO rats (N = 5) when compared to BUO control rats. We conclude that: (1) endothelin-1 has a significant vasoconstrictor role in rats with BUO of 24 hours duration and accounts for a portion of the decrease in glomerular filtration rate seen in rats after unilateral release of bilateral ureteral obstruction, and (2) in the BUO setting, the net role of the renal artery endothelium is vasodilatory.     

Probucol improves erectile function by regulating endoplasmic reticulum stress in rats with streptozotocin-induced diabetes

This study was to explore the effect and mechanism of Probucol on STZ-induced erectile dysfunction in diabetic rats. Thirty SD male rats aged 12 weeks were given intraperitoneal injection of STZ after fasting for 12 hr. Diabetic rats were haphazardly partitioned under two assemblies and administered 0 or 500 mg/kg probucol by oral gavage to 12 weeks. Control group was intraperitoneally injected with physiological saline, and saline was administered by oral gavage daily. Intracorporeal pressure was used to evaluate erectile function. Levels of proteins were detected using immunohistochemistry and Western blotting. α-SMA and vWF were detected using immunofluorescence staining. After treatment, erectile function in probucol group was significantly improved. Endoplasmic reticulum stress-related proteins were expressed higher in DM group than in sham group, while expression of these proteins decreased significantly in probucol group. However, α-SMA and vWF were expressed at lower levels in DM group than in sham group, and probucol treatment reversed this phenomenon. Finally, Bax and Caspase3 were expressed at higher levels and Bcl-2 was expressed at lower levels in DM group, while the opposite result was obtained in probucol group. In conclusions, probucol improves erectile function by reducing endothelial dysfunction and inhibiting PERK/ATF4/CHOP pathway in STZ-induced diabetic rats.     

氧化应激介导糖尿病大鼠肾小管上皮细胞转分化及普罗布考的干预作用

目的 研究氧化应激在糖尿病肾病（DN）大鼠肾小管上皮细胞转分化中的作用,探讨抗氧化剂普罗布考对大鼠DN的肾脏保护作用。 方法 30只雄性SD大鼠随机分为正常对照组、DN组和普罗布考干预组（1％普罗布考饮食）,每组10只。分别于第3周、第8周及第12周检测24 h尿蛋白（UTP）;12周末检测各组大鼠血糖、血脂（胆固醇、三酰甘油）、Scr、肌酐清除率（Ccr）、肾脏组织匀浆液丙二醛（MDA）含量及谷胱甘肽过氧化物酶（GSH-Px）活性。肾组织病理切片行 HE和Masson染色;采用免疫组化和Western印迹检测肾组织核转录因子Sp1、α平滑肌肌动蛋白（α-SMA）及E钙黏蛋白（E-cadherin）表达。 结果 与正常对照组比较,DN组血糖、Scr、肾组织匀浆MDA和24 h UTP水平显著增高（均P < 0.01）,Ccr显著降低（P < 0.01）;肾组织肾小管损伤分数、α-SMA和 Sp1蛋白表达水平明显增高（均P < 0.01）;肾组织E-cadherin蛋白表达明显下调。肾组织MDA含量分别与α-SMA及Sp1蛋白表达呈正相关（r ＝ 0.896,P < 0.01;r ＝ 0.862,P < 0.01）,与E-cadherin蛋白表达呈负相关（r = -0.673, P < 0.01）。普罗布考干预组Scr、24 h UTP、肾组织MDA、肾小管损伤分数及肾组织α-SMA、 Sp1蛋白表达水平较DN组均明显降低（均P < 0.01）;Ccr和肾组织E-cadherin蛋白表达水平较DN组均明显增加（均P < 0.01）。 结论 氧化应激在DN大鼠肾小管上皮细胞转分化中起重要作用。普罗布考可能通过抗氧化、下调肾组织Sp1蛋白表达及抑制肾小管上皮细胞转分化延缓DN大鼠肾脏病变进展。     

西罗莫司对双侧输尿管梗阻大鼠水电解质代谢紊乱的保护作用

目的 探讨西罗莫司对双侧输尿管梗阻(BUO)大鼠水电解质代谢紊乱及肾脏上皮钠通路γ(γ-ENaC)、Na+-K+-ATP酶及水通道蛋白2(AQP2)蛋白的影响.方法 Wistar大鼠48只,随机分为假手术组、BUO组和西罗莫司组,每组16只.BUO组和西罗莫司组大鼠结扎双侧输尿管制作BUO模型,假手术组仅游离双侧输尿管后缝合.BUO组及西罗莫司组双侧输尿管梗阻24 h后解除梗阻.西罗莫司组每天西罗莫司口服液(2.5 ml/次)灌胃,假手术组及UUO组用同体积生理盐水灌胃.于术后4、7d测量3组大鼠尿量并留取尿液进行生化分析;术后4、7d抽取动脉血化验,同时取出双侧肾脏,采用免疫组化及蛋白质印迹法检测肾脏γ-ENaC、Na+-K+-ATP酶及AQP2蛋白的表达.结果 BUO组大鼠输尿管梗阻解除后4、7d尿量分别为(85.31±13.15)、( 66.39±10.56)ml,显著多于假手术组( 35.36±7.74)、(33.90±8.03)ml及西罗莫司组(69.81±10.70)、(48.57±9.01)ml;尿钠浓度(42.17±7.35)、(43.63±18.39) mmol/L,显著低于假手术组(170.56±18.39)、(172.52±7.35) mmol/L及西罗莫司组(76.18±13.20)、(134.28±13.20) mmol/L,3组间比较差异均有统计学意义(P＜0.05).西罗莫司组4、7d肾脏γ-ENaC表达量分别为2.09±0.32、2.27±0.35,Na+ -K+ -ATP酶分别为2.41±0.48、2.67±0.43,AQP2分别为2.17±0.45、2.63±0.28,显著高于同时间点的BUO组(1.28±0.21、1.45±0.17,1.99±0.28、2.18±0.24,0.93±0.22、1.31±0.16),低于同时间点假手术组(2.58±0.51、2.60±0.56,2.89±0.53、2.97±0.66,3.05±0.63、3.10±0.67),3组间比较差异均有统计学意义(P＜0.05).结论 γ-ENaC、Na+-K+-ATP酶及AQP2蛋白水平降低可能是泌尿系梗阻后肾小管性钠回吸收障碍、低渗性尿量增多的主要原因之一.西罗莫司可以通过抑制肾小管γ-ENaC、Na+-K+-ATP酶及AQP2蛋白丢失,减轻术后肾脏钠回吸收障碍及低渗性尿等水电解质代谢紊乱,保护肾脏功能.     

Carvedilol, an antihypertensive drug with antioxidant properties, protects against glycerol-induced acute renal failure

BACKGROUND/AIMS: The pathogenesis of glycerol-induced myoglobinuric acute renal failure involves, among other causes, ischaemia, vascular congestion and reactive oxygen metabolites. The aim of this study was to investigate the role of carvedilol, an antihypertensive drug with antioxidative potential, in glycerol-induced acute renal failure in rats. METHODS: Three groups of rats were employed in this study. Group 1 served as control, group 2 was given 50% glycerol (8 ml/kg, i.m.) and group 3 was given glycerol plus carvedilol (3 mg/kg, i.p.). Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and enzymatic activity of catalase, glutathione reductase and superoxide dismutase. RESULTS: Glycerol treatment resulted in marked renal oxidative stress and significantly deranged renal functions. Both of these factors were significantly improved by carvedilol treatment. Carvedilol, by its interaction with Fenton reaction chemistry and radical scavenging activity, protected the kidney against the oxidative stress and resultant renal dysfunction produced by glycerol. CONCLUSION: Based on these results, this study indicates the protective effect of carvedilol in this rhabdomyolysis-mimicking model.     

普乐布考治疗慢性肾脏疾病的疗效观察

目的观察普罗布考对以肾小动脉硬化为主要病变的慢性肾脏疾病（CKD）的治疗作用。方法采用回顾性对比分析．观察52例病因为为高血压肾病和糖尿病肾脏病的CKD患者服用普罗布考的疗效。并设对照组49例。两组基础疾病及基本治疗相似,对照组未用普罗布考,观察9个月。应用硫代巴比妥酸比色法测定血清丙二醛（malondialdehyde,MDA）;常规生化疗法检测尿蛋白定量、肾功能（GFR、BUN、SCr）及血脂（TC、TG）;用Friedwald公式计算低密度脂蛋白胆固醇（LDLC）.采用方差分析及t检验进行统计学处理。结果观察9个月后,治疗组MDA、TC、TG、LDL-C、均下降,尿蛋白定量减少,CIFR、BUN及SCr等指标改善。对照组MDA、血脂无变化。结论普罗布考能够通过抗氧化应激及降脂作用减轻高血压肾脏病和糖尿病肾病的肾脏损伤,延缓CKD进展。     

Vitamin E protects renal antioxidant enzymes and attenuates glomerulosclerosis in Adriamycin-treated rats

BACKGROUND/AIMS: In the rat Adriamycin model of chronic renal failure, the development of glomerulosclerosis and tubulointerstitial lesions is accompanied by decreased activities and mRNA levels of the antioxidant enzymes. In this study, we investigated the effect of oral vitamin E supplementation on antioxidant enzyme activities in both the cortex and isolated glomeruli from Adriamycin-treated rats. METHODS: Glomerulosclerosis, tubulointerstitial lesions and ferric iron deposits were evaluated by histochemical staining methods, and antioxidant enzyme activities were measured by spectrophotometry. RESULTS: Vitamin E supplementation of the normal diet attenuates Adriamycin-induced glomerulosclerosis and tubulointerstitial lesions, but not proteinuria and serum total cholesterol, low-density lipoprotein cholesterol, triglycerides and total protein concentrations. In the cortex, vitamin E completely prevented a decrease in enzyme activity for Cu/Zn superoxide dismutase and catalase, and partly for Mn superoxide dismutase and glutathione peroxidase. In the glomeruli, vitamin E completely prevented a decrease in activity for Cu/Zn superoxide dismutase, catalase and glutathione peroxidase, and partly for Mn superoxide dismutase. CONCLUSION: Dietary supplementation of vitamin E protects the activities of antioxidant enzymes in the kidney cortex and glomeruli, and attenuates the evolution towards terminal renal failure in rats treated with Adriamycin.     

Altered antioxidant defence in a mouse adriamycin model of glomerulosclerosis.

BACKGROUND: Antioxidant enzyme status changes in experimental models of chronic renal disease with glomerulosclerosis. Most of the studies are performed in rats. We now investigate whether a mouse model with more rapid development of glomerulosclerosis is suitable for the study of radical-associated renal disease. METHODS: Female BALB/c mice are injected intravenously with a single dose of adriamycin (10 mg/kg). The development of glomerular and interstitial injury is evaluated by means of renal function parameters and histology. Renal cortex activities of catalase, Cu/Zn and Mn superoxide dismutase and glutathione peroxidase are measured by enzymatic techniques, and their mRNA levels by Northern blot analysis. RESULTS: The mice develop proteinuria and hypercholesterolaemia; glomerulosclerosis is present 20 days after adriamycin injection. Involvement of reactive oxygen intermediates in the disease process is supported by an increased cortex level of glutathione (1.77+/-0.13 vs 1.31+/-0.12 micromol/g kidney; P = 0.021) and ferric iron deposition in the tubulointerstitial compartment. Glomerulosclerosis and tubulointerstitial lesions are accompanied by decreased cortex activities of catalase (0.19+/-0.01 vs 0.23+/-0.01 U/mg protein; P = 0.024), glutathione peroxidase (0.28+/-0.01 vs 0.32+/-0.01 U/mg protein; P = 0.049) and Mn superoxide dismutase (6.61+/-0.91 vs 9.25+/-0.99 U/mg protein, P = 0.020). We find decreased cortex mRNA levels only for glutathione peroxidase. CONCLUSION: The fast development of glomerulosclerosis combined with an altered antioxidant status makes this mouse adriamycin model a suitable alternative for the slower rat models.     

Antioxidant enzyme gene expression in rats with remnant kidney induced chronic renal failure

Reactive oxygen intermediates play a role in chronic renal injury and glomerulosclerosis. We investigate changes in renal cortex antioxidant enzyme gene expression in the rat remnant-kidney model of chronic renal failure and compare the new data to enzyme activities published earlier. Antioxidant enzyme gene expression is evaluated by Northern blot analysis of cortex mRNA, using cDNA probes for catalase, copper/zinc-containing superoxide dismutase, and glutathione peroxidase. Catalase gene expression decreases during development of renal failure; this decrease is accompanied by decreased catalase activity during the glomerulosclerosis phase of the remnant-kidney model. Copper/zinc superoxide dismutase and glutathione peroxidase gene expression remain at a normal level during progression of the model, whereas their activities show a temporary decrease in the early remnant kidney. In the remnant-kidney model, catalase seems to be more vulnerable to reactive oxygen intermediates than superoxide dismutase and glutathione peroxidase. Our results show that antioxidant enzyme activity and gene expression do not change in the same direction at all times during disease development and that all antioxidant enzymes do not respond in the same way.