Improvement of Hyperlipidemia and Proteinuria without Noticeable Growth Retardation by Feeding a Methionine and Threonine Supplemented Low-casein Diet to Nephritic Rats

We have previously demonstrated that low-casein diets supplemented with cystine and threonine reduced hyperlipidemia and proteinuria in nephritic rats without noticeable protein malnutrition. In the present study, we examined whether or not a low-casein diet supplemented with methionine, sulfur amino acid other than cystine, and threonine would ameliorate the symptoms without protein malnutrition in rats with nephrotoxic serum nephritis by feeding experimental diets for 10 days. A methionine-threonine-supplemented 8.5% casein diet (8.5 CMT), when compared with a basal 20% casein diet, improved hypoalbuminemia as well as hyperlipidemia and proteinuria without noticeable growth retardation and fatty liver induction in nephritic rats. Fecal bile acid excretion and microsomal cholesterol 7α-hydroxylase activity were enhanced by 8.5CMT feeding. These results suggest that amino acid-balanced low protein diet would have a beneficial effect on the symptoms of nephritis. They also suggest that the hypocholesterolemic action of 8.5CMT may be, at least in part, due to increased fecal bile acid excretion accompanied by elevated microsomal cholesterol 7α-hydroxylase activity.     

Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.     

Dietary soy protein reduces early renal disease progression and alters prostanoid production in obese fa/fa Zucker rats

With the rising incidence of obesity and the metabolic syndrome, obesity-associated nephropathy also has increased. One of the earliest pathologies in the development of this nephropathy is glomerular hyperfiltration and hypertrophy. Dietary soy protein (SP) ameliorates disease progression in several models of renal disease, and vegetable sources of protein, as compared to animal sources of protein, alter renal hemodynamics. Therefore, the effect of dietary SP on early renal disease and prostanoid production was examined in the obese fa/fa Zucker rat. Rats, 6 weeks of age, were given diets containing 17% protein from either SP or egg white (EW) for 8 weeks. Feed consumption and body and kidney weights were significantly greater in fa/fa rats as compared to lean rats. The fa/fa rats also had 139% more proteinuria and kidneys with 43% larger glomeruli. SP feeding did not alter body weights or proteinuria but did result in 6% lower kidney weights (g/100 g body weight) and 16% smaller glomeruli in fa/fa rats. Cyclooxygenase activity as determined by 6-keto prostaglandin F(1alpha) (6-keto PGF(1alpha)) synthesis was lower in fa/fa rats given SP-based diets as compared to those given EW-based diets. Ratios of renal thromboxane (TX) B(2)/6-keto PGF(1alpha) and PGE(2)/6-keto PGF(1alpha) were higher, while TXB(2)/PGE(2) levels were not different in rats given SP diets as compared to those given EW diets, also indicating that dietary SP reduced renal 6-keto PGF(1alpha) levels. These findings suggest that attenuation of early glomerular hypertrophy in young obese fa/fa rats by dietary SP may be mediated by the lower levels of 6-keto PGF(1alpha) since this would be expected to reduce glomerular hyperfiltration.     

A new mouse strain manifesting high proteinuria and kidney glomerular defect.

A mutant strain of mice manifesting high proteinuria, wasting syndrome, and kidney glomerular defect was established from the F5 offspring of an interstrain cross of CBA/Nga and RFM/Nga mice. Affected mice had high levels of proteinuria after 40 days of age. The body weight of about 22.6% of affected mice decreased rapidly and they died between 3 and 5 months of age. We learned that this abnormality is controlled by two pairs of autosomal recessive genes; the mutant strain of mice is designated FGS/Nga. The mutant strain has been characterized by high proteinuria and renal lesions with focal sclerosis of glomeruli and tubular atrophy with interstitial nephritis in the kidney resembling the human disease. The FGS/Nga mouse strain is a potential animal model for studying kidney glomerular defect in humans.     

应用高脂饮食联合维生素D3建立慢性系膜增殖性肾炎血管病变大鼠模型

目的 探讨应用高脂饮食建立慢性系膜增殖性肾炎血管病变模型的方法.方法 雄性Wistar大鼠行单侧肾切除后随机分为单纯肾切除组、单纯肾炎组、单纯高脂组、肾炎高脂组.单纯肾炎组、肾炎高脂组在单侧肾切除后3d尾静脉注射OX7抗体(100 mg/kg),1周后尾静脉连续注射OX7抗体(每次100 mg/kg,1次/周,共3次),单纯肾切除组和单纯高脂组在同一时间尾静脉注射PBS,注射抗体后第2天单纯高脂组、肾炎高脂组腹腔注射维生素D3(6万U/kg,1次/4周),同时给予高脂饲料.分别于第4、8、10周观察各组大鼠的一般情况、体重、血压、尿蛋白、血浆白蛋白、血脂、血钙、肾功能以及肾脏病理改变.结果 模型组(肾炎高脂组)大鼠第8周肾小球外的小动脉出现管壁增厚,管腔变小,平滑肌细胞减少,细胞排列紊乱,纤维组织增生.第10周单纯肾炎组和单纯高脂组肾小球外小动脉管壁轻度增厚,管腔变化不明显,模型组血管病变积分明显高于单纯肾炎组和单纯高脂组(P＜0.05).结论 通过对慢性抗Thy1肾炎大鼠加用高脂饲料并腹腔注射维生素D3的方法,可以成功建立慢性系膜增殖性肾炎血管病变模型.     

Hypolipidemic action of dietary resveratrol,a phytoalexin in grapes and red wine,in hepatoma-bearing rats

Resveratrol is an antioxidant present in grapes and their related products. We investigated whether dietary resveratrol could inhibit the proliferation and metastasis of tumors and hyperlipidemia in Donryu rats subcutaneously implanted with an ascites hepatoma cell line of AH109A. By feeding 10 or 50 ppm resveratrol in the diet to hepatoma-bearing rats for 20 days, solid tumor growth and metastasis tended to be suppressed dose-dependently. Resveratrol (50 ppm) significantly suppressed the serum lipid peroxide level, indicating its antioxidative properties or those of its metabolite(s) in vivo. Resveratrol dose-dependently suppressed both the serum triglyceride and very-low-density lipoprotein + low-density lipoprotein (VLDL + LDL)-cholesterol levels. The hypocholesterolemic action of resveratrol is attributed, at least in part, to an increased excretion of neutral sterols and bile acids into feces. These results suggest that dietary resveratrol is hypolipidemic with a tendency for anti-tumor-growth and anti-metastasis effects in hepatoma-bearing rats.     

Stimulatory effect of calcium administration on regucalcin mRNA expression is attenuated in the kidney cortex of rats ingested with saline

The expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats ingested with saline was investigated. The alteration in regucalcin mRNA levels was analyzed by Northern blotting using liver regucalcin complementary DNA (0.9 kb of open reading frame). Rats were freely given saline as drinking water for 7 days. Regucalcin mRNA levels in the kidney cortex were suppressed by saline ingestion. When calcium chloride (10 mg Ca/100 g body weight) was intraperitoneally administered to rats ingested with saline for 7 days, the effect of calcium administration to increase regucalcin mRNA levels was weakened by saline ingestion. Such effect was also seen by the administration of 2.5 and 5 mg Ca/100 g. Regucalcin mRNA levels in the kidney cortex of spontaneous hypertensive rats (SHR) were not appreciably increased by the administration of calcium (10 mg/100 g). Meanwhile, calcium content in the kidney cortex was significantly elevated by the administration of calcium (10 mg/100 g) to normal rats. This increase was weakened in saline-ingested rats. Moreover, Ca²⁺/calmodulin-dependent protein kinase activity in the cytosol of kidney cortex was significantly decreased by saline ingestion. These results suggest the possibility that saline ingestion-induced suppression of regucalcin mRNA expression in the kidney cortex is partly involved in the attenuation of Ca²⁺ signalling.     

白藜芦醇通过调节SIRT1/NF-κB通路减轻力竭训练致大鼠肾脏炎症反应

白藜芦醇是天然存在的沉默信息调节因子2相关酶1(sirtuin1，SIRT1)小分子激动剂，其肾的保护作用已在多种肾疾病动物模型中得到了验证。然而，白藜芦醇是否能够改善力竭训练导致的大鼠肾损伤，以及是否通过SIRT1/NF κB信号通路调节运动性肾损伤大鼠肾炎症反应，尚缺乏系统研究。本研究将32只SD大鼠随机分为安静对照组(Con组)，白藜芦醇组（Rsv组），力竭运动组（Ex组），力竭运动+白藜芦醇组（Ex+Rsv组）。Rsv和Ex+Rsv组每天灌胃50 mg/kg体重剂量的白藜芦醇， Ex和Ex+Rsv组进行4周力竭训练，最后1次训练后24 h取材。本研究结果显示，与Con组相比，Ex组大鼠Scr（175.66 ± 16.08 vs.153.34 ± 8.67，P < 0.01）、BUN（6.67 ± 0.53 vs.5.37 ± 019，P < 0.01）和尿NGAL（9.01 ± 0.18 vs.7.48 ± 0.31，P < 0.01）水平均显著升高，Ex组大鼠肾组织NF κB P65在蛋白质水平表达显著升高（0.77 ± 010 vs. 0.27 ± 0.03，P < 0.01）；各组大鼠肾组织SIRT1在蛋白质水平表达上，Rsv组显著高于Con组（0.90 ± 0.14 vs. 0.43 ± 0.15，P < 0.05），Ex+Rsv组显著高于Ex组（1.0 ± 0.28 vs. 0.38 ± 0.12，P< 001）；与Ex组相比，Ex+Rsv组大鼠肾组织NF-κB P65（0.57 ± 0.13 vs. 0.77 ± 0.10，P < 0.05）和Ac-NF-κB P65（0.52 ± 0.13 vs. 0.78 ± 0.11，P < 0.05）在蛋白质水平表达显著降低。以上结果表明，4周大强度力竭运动导致大鼠出现运动性肾损伤，并激活大鼠肾NF-κB的表达。白藜芦醇可显著提高大鼠肾组织SIRT1在蛋白质水平的表达，并增加脱乙酰化作用，降低NF-κB P65蛋白质乙酰化修饰水平，进一步降低NF-κB的表达。白藜芦醇减轻力竭训练致大鼠肾的炎症反应的机制可能与SIRT1/NF-κB通路有关。     

Experimental nephrotic syndrome in the rat. Biologic parameters and study of several hydrolases in different purified kidney fractions]

The induction of nephrotoxic nephritis in rats with rabbit antibodies preparation results in proteinuria, hypoproteinemia and hyperlipidemia with little glomerular lesions. A study of some hydrolases in cortex and medulla on one hand and glomerular and tubules on the other, showed changes in the activities of following enzymes. 1) A 20-30 % decrease in Na+, K+ dependent ATP-ase in whole kidney. 2) A 20 % decrease in beta-galactosidase activity in glomerular and medulla. 3) A 20 % increase of arylsulphatase A activity in tubules. These results are discussed in the light of the present knowledge of sulphatide metabolism in kidney.     

Proteinuria in long term streptozotocin diabetes in rats

The total protein excretion rate of Munich-Wistar rats studied 80–90 days after the induction of diabetes with streptozotocin was more than double that of age-matched controls. The urine proteins consisted of only albumin and pre-albumin fractions. Dextran/inulin clearance ratios were not higher in the diabetic rats, and it is concluded that the proteinuria is not due to an increased glomerular permeability to protein. Kidney size was increased 1.7 fold and body weight was 60% of control. Glomerular filtration rate uncorrected for kidney or body weight was also not different from controls.     

不同剂量白藜芦醇对糖尿病性白内障大鼠晶状体抗氧化酶活力的影响

目的:探究不同剂量白藜芦醇对糖尿病性白内障大鼠晶状体抗氧化酶活力的影响。方法:75只5周龄健康SPF级雄性SD大鼠按照随机数字表法分为正常对照组、模型组,白藜芦醇低剂量组,白藜芦醇中剂量组和白藜芦醇高剂量组,每组各15只。五组大鼠均给予常规适应性喂养,模型组和白藜芦醇低、中、高剂量组大鼠采用链脲佐菌素(STZ)以60 mg/kg的给药剂量制作糖尿病大鼠模型,成模后白藜芦醇低剂量组按20 mg/kg、白藜芦醇中剂量组按50 mg/kg、白藜芦醇高剂量组按100 mg/kg的给药剂量每日给予白藜芦醇灌胃。观察12周后5组大鼠晶状体的混浊程度,检测血糖、体重后处死大鼠,检测晶状体内超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)以及过氧化氢酶(CAT)的活性改变。结果:随着白藜芦醇剂量的升高,白藜芦醇低、中、高剂量组大鼠的血糖逐渐降低而体重逐渐升高,且组间比较均具有统计学差异(P0.05)。三组不同剂量白藜芦醇干预组大鼠晶状体的浑浊程度均低于模型组,且白藜芦醇高剂量组大鼠晶状体的浑浊程度最低,差异均具有统计学意义(P0.05)。白藜芦醇低、中、高剂量组大鼠SOD、GSH-PX和CAT酶活力与模型组大鼠相比均明显升高,而与正常对照组相比均明显降低(均P0.05)。随着白藜芦醇剂量的升高,白藜芦醇低、中、高剂量组大鼠SOD、GSH-PX和CAT酶活力逐渐升高,且组间比较均具有统计学差异(P0.05)。结论:高剂量白藜芦醇可更为明显地降低血糖浓度,提高晶状体SOD、GSH-Px及CAT酶活力,改善糖尿病性白内障晶状体的浑浊程度。     

Lipid peroxidation in the kidneys of rats with nephritis induced by nephrotoxic serum and proteinuria induced by albumin overload]

Lipid peroxidation (LPO) stimulated by ascorbate was studied in renal cortex of 20 rats with nephrotoxic nephritis (NTN) and of 9 rats with proteinuria induced by a 3-day course of i. p. injections of the human serum albumin. At the early stages of NTN (0.5 h. and 3 h.) LPO activities were of the same values as in control rats. A small decrease in renal cortex LPO was found on the 4-th day of NTN when nephrotic syndrome has been developed. A significant reduction in LPO activity was observed on the 16-th day of NTN characterized by a more pronounced nephrotic syndrome. LPO activity in renal cortex of the rats with albumin overload proteinuria was also reduced. An inhibitory effect of proteinuria on LPO activity in kidney is discussed.     

Effects of different doses of resveratrol on body fat and serum parameters in rats fed a hypercaloric diet

Recently resveratrol, a compound naturally occurring in various plants, has been proposed as a potential anti-obesity compound. The aim of the present work was to analyse the effects of different doses of resveratrol on body fat and serum parameters in rats. Thirty-two male Sprague-Dawley rats were randomly divided into four groups and fed on a hypercaloric diet for 6 weeks. The doses oftrans-resveratrol used were 6, 30 and 60 mg/kg body weight/d in RSV1, RSV2 and RSV3 groups respectively. The stability of resveratrol when added to the diet was evaluated. Blood samples were collected, and white adipose tissue from different anatomical locations, interscapular brown adipose tissue, gastrocnemious muscles and liver were weighed. Commercial kits were used to measure serum cholesterol, glucose, triacylglycerols and non-esterified fatty acids. While the lowest dose did not have a body fat reducing effect, the intermediate dose reduced all the white adipose depots. The highest dose significantly reduced mesenteric and subcutaneous depots but not epididymal and perirenal tissues. Although the reduction in all the anatomical locations analysed was 19% in the RSV3 group, in the RSV2 group it was 24%. No significant differences among the experimental groups were found in brown adipose tissue, gastrocnemious muscle or liver weights. Serum parameters were not affected by resveratrol intake because no differences among the experimental groups were observed. These results suggest that resveratrol is a molecule with potential anti-obesity effect. The most effective of the three experimental doses was 30 mg/kg body weight/d.     

Calcium-binding protein regucalcin mRNA expression in the kidney cortex is suppressed by saline ingestion in rats

The effect of adrenalectomy (ADX) or saline ingestion, which is a hypertensive factor, on the expression of calcium-binding protein regucalcin mRNA in the kidney cortex of rats was investigated. The change of regucalcin mRNA levels was analyzed by Northern blotting using rat liver regucalcin complementary DNA (0.9 kb of open-reading frame). Regucalcin mRNA was expressed in the kidney cortex but not the medulla. Rats were adrenalectomized, and 48 h later they were sacrificed. ADX caused a reduction of regucalcin mRNA levels in the kidney cortex, suggesting that adrenal glands participate in the regulation of the mRNA expression. This reduction was not restored by the subcutaneous administration of dexamethasone with an effective dose (1 mg/kg body weight), which can stimulate kidney regucalcin mRNA expression. Regucalcin mRNA levels in the kidney cortex of rats were markedly suppressed by the ingestion of saline for 7 days. The ADX-induced decrease of renal cortex regucalcin mRNA levels was not appreciably restored by saline ingestion. Moreover, regucalcin mRNA levels in the kidney cortex of spontaneous hypertensive rats (SHR) were clearly decreased as compared with that of control (Wistar-Kyoto) rats. Meanwhile, calcium content in the kidney cortex was not significantly decreased by ADX or saline ingestion. The present study suggests that the expression of regucalcin mRNA in the kidney cortex of rats is suppressed by saline administration.     

Influence of nutritional factors on the renotrophic action of ACTH in the uninephrectomized rat.

In the rat, renal compensatory hypertrophy (RCH) was apparent 48 h after uninephrectomy; it was significantly enhanced by long-acting beta1-24-corticotrophin (ACTH) when the animals had free access to food and a NaCl solution (9 g/l). In rats starved after uninephrectomy but drinking the NaCl solution freely, RCH was suppressed: the weights of the body, heart, liver, and solitary kidney were reduced. In similarly starved rats treated with ACTH, the weights of the heart and the solitary kidney were normal. RCH was also impaired in rats fed only a glucose solution (30 g/dl) after uninephrectomy, but it is restored by ACTH, which significantly increases the weight of the remaining kidney. This renotrophic action of ACTH may be related to hyperglycemia and, perhaps, elevated urinary K excretion, which occur in hyper-adrenocorticism and increase the work load of the nephron.     

Dyslipoproteinemia in an inbred rat strain with spontaneous chronic progressive nephrotic syndrome.

Rats of the Milan Normotensive Strain (MNS) develop a dyslipoproteinemia that is associated with a spontaneous, age-dependent and slowly progressive nephropathy characterized by proteinuria and hypoalbuminemia (nephrotic syndrome). We assumed that the MNS strain might be a suitable model for studying the features of nephrotic dyslipoproteinemia and its relationship with proteinuria, hypoalbuminemia, and hepatic apolipoprotein production. Plasma lipoproteins were investigated in MNS rats at various ages (4-48 weeks) and in another rat strain (Milan Hypertensive Strain, MHS), genetically related to MNS but free of nephropathy, that was used as control. In MNS rats, abnormal proteinuria was detectable at 20 weeks and increased 2-fold up to 34 weeks with no reduction of plasma albumin (compensated stage). During this stage we found increased levels of plasma cholesterol (+ 34%), high density lipoprotein-1 (HDL1) (+ 73%), and HDL2 (+ 31%) that were positively correlated with proteinuria but not with plasma albumin. The later stage (34-48 weeks) (nephrotic stage) was characterized by a further increase of proteinuria, moderate hypoalbuminemia (- 25%), a 2-fold increase of plasma cholesterol, triacylglycerols, low density lipoprotein (LDL), and HDL1, and a 1.2-fold increase of HDL2. In this stage the levels of LDL, HDL1, and HDL2 were positively correlated with proteinuria, and negatively correlated with plasma albumin. The most striking change in apolipoproteins was a progressive increase of the relative content of apoA-I in HDL (in 48-week-old MNS rats the A-I/E ratio was 3-fold that found in MHS rats) that was associated with a similar increase of plasma apoA-I. None of these lipoprotein changes were observed in age-matched MHS rats. At the end of the compensated stage, the hepatic levels of A-I, B, A-II, and albumin mRNA were 5.3-, 3.5-, 1.3-, and 2.0-fold, respectively, those found in age-matched MHS rats. During the nephrotic stage, albumin mRNA continued to increase, whereas A-I, B, and A-II mRNAs decreased toward the levels found in age-matched MHS rats. Thus, nephrotic dyslipoproteinemia in MNS rats starts to develop in the compensated stage before the onset of hypoalbuminemia, is characterized by an early elevation of HDL1 + HDL2, and is associated with an increased content of hepatic mRNAs of some apolipoproteins, especially apoA-I. The slow progression of nephrotic syndrome with the long-standing proteinuria and no reduction in plasma albumin renders the MNS strain the most suitable animal model for the study of the effect of proteinuria on plasma lipoprotein metabolism.     

Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO3.

Free radical scavengers can protect against the genotoxicity induced by chemical carcinogens by decreasing oxidative damage. The protective effect of the antioxidants melatonin, resveratrol, vitamin E, butylated hydroxytoluene and 2-mercaptoethylamine, and the spin-trapping compound alpha-phenyl-N-tert-butyl nitrone (PBN) against oxidative DNA damage was studied in the kidney of rats treated with the kidney-specific carcinogen potassium bromate (KBrO3). KBrO3 was given to rats previously treated with melatonin, resveratrol, PBN, vitamin E, butylated hydroxytoluene, or 2-mercaptoethylamine. Oxidative damage to kidney DNA was estimated 6 hours afterwards by measuring 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxo8dG) referred to deoxyguanosine (dG) by means of high performance liquid chromatography with electrochemical-coulometric and ultraviolet detection. Levels of oxo8dG in the renal genomic DNA significantly increased by more than 100% after the KBrO3 treatment. This increase was completely abolished by the treatment with resveratrol and was partially prevented by melatonin, PBN and vitamin E. Resveratrol and PBN also prevented the increase in relative kidney weight induced by KBrO3. These results show that various different antioxidants and a free radical trap, working in either the water-soluble or the lipid-soluble compartments, can prevent the oxidative DNA damage induced in the kidney by the carcinogen KBrO3.     

Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation.     

Cytochrome P450 2B1 mediates complement-dependent sublytic injury in a model of membranous nephropathy

Membranous nephropathy is a disease that affects the filtering units of the kidney, the glomeruli, and results in proteinuria accompanied by loss of kidney function. Passive Heymann nephritis is an experimental model that mimics membranous nephropathy in humans, wherein the glomerular epithelial cell (GEC) injury induced by complement C5b-9 leads to proteinuria. We examined the role of cytochrome P450 2B1 (CYP2B1) in this complement-mediated sublytic injury. Overexpression of CYP2B1 in GECs significantly increased the formation of reactive oxygen species, cytotoxicity, and collapse of the actin cytoskeleton following treatment with anti-tubular brush-border antiserum (anti-Fx1A). In contrast, silencing of CYP2B1 markedly attenuated anti-Fx1A-induced reactive oxygen species generation and cytotoxicity with preservation of the actin cytoskeleton. Gelsolin, which maintains an organized actin cytoskeleton, was significantly decreased by complement C5b-9-mediated injury but was preserved in CYP2B1-silenced cells. In rats injected with anti-Fx1A, the cytochrome P450 inhibitor cimetidine blocked an increase in catalytic iron and ROS generation, reduced the formation of malondialdehyde adducts, maintained a normal distribution of nephrin in the glomeruli, and provided significant protection at the onset of proteinuria. Thus, GEC CYP2B1 contributes to complement C5b-9-mediated injury and plays an important role in the pathogenesis of passive Heymann nephritis.