Treatment of experimental immune complex glomerulonephritis by sodium alginate

We have studied the therapeutic efficacy of the sodium alginate in experimental immune complex glomerulonephritis. Bovine serum albumin (BSA) nephritis was induced in rats by a subcutaneous immunization and daily intravenous administration of BSA. Sodium alginate at two different doses (25 and 50 mg/kg) was administered intraperitoneally at regular 72-h intervals for 6 weeks. Onset of treatment was day 42. Urinary protein was measured weekly and serum anti-BSA antibody was assessed by ELISA method at different intervals. Animals were euthanized at the 12th experimental week and blood samples and kidney specimens were obtained. BUN, serum creatinine and serum cholesterol and triglyceride were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. The tolerability and inhibitory effect of LVA on matrix metalloproteinase 2 (MMP-2) were tested using WEHI-164 cell line and zymography method. Results of this experiment showed that treatment with sodium alginate could significantly reduce the urinary protein excretion and serum creatinine in treated rats vs. nontreated controls. Anti-BSA antibody titers were lower in treated rats than in controls at the 12th week post-immunization. There was no significant difference in the level of BUN and serum lipids between two groups. Whereas, glomerular hypercellularity, PMN infiltration and glomerular deposition of BSA were less intense in treated rats vs. controls. Moreover, in vitro examinations revealed that treatment with LVA, as a very safe agent could diminish MMP-2 activity. These results suggest that treatment with sodium alginate as a new immunosuppressive agent can reduce proteinuria, inhibit MMP-2 activity and suppress the antibody production as well as the development of glomerular lesions in a rat model of immune complex glomerulonephritis.     

Production of M2000 (β-d-mannuronic acid) and its therapeutic effect on experimental nephritis

The present research introduces the method of Production of M2000 (β-d-mannuronic acid) and its therapeutic effect on experimental model of nephritis. M2000 was produced using enzymatic and chemical procedure on prepared alginate from Pseudomonas fluorescens. The experimental glomerulonephritis was induced in rats by a subcutaneous immunization and daily intravenous administration of bovine serum albumin (BSA). M2000 solution (30mg/kg) was administered intraperitoneally at regular 48-h intervals for 4 weeks. Onset of treatment was day 56. Urinary protein was measured weekly and serum anti-BSA antibody was assessed by ELISA method at different intervals. Animals were killed on day 84 and blood samples and kidney specimens were obtained. Serum (creatinine, BUN, cholesterol, and triglyceride) and urine (protein, urea, and creatinine) determinants were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. The fibrosarcoma cell line was used for assaying tolerability and matrix metalloproteinase type 2 (MMP-2) activity. MMP-2 activity was assessed using zymography. Our data showed that M2000 therapy could significantly reduce the urinary protein excretion in treated rats versus non-treated controls. Anti-BSA antibody titer was lower in treated rats than in controls at the 12th experimental week. PMN infiltration and glomerular immune complex deposition was less intense in treated rats than in controls. Cytotoxicity analysis of M2000 showed a much higher tolerability compared with other tested drugs (diclofenac, piroxicam and dexamethasone). The inhibitory effect of M2000 in MMP-2 activity was significantly greater than that of dexsamethasone and of piroxicam at a concentration of 200μg/ml. Moreover, the toxicological study revealed that M2000 had no influence on serum (BUN, creatinine, triglyceride and cholesterol) determinants, urinary protein excretion and glomerular histology in healthy group receiving drug. Conclusions: In this research, for the first time we introduced the procedure of production of M2000 (β-d-mannuronic acid) and our data suggest that treatment with M2000, as a novel anti-inflammatory drug can reduce proteinuria, diminish antibody production and suppress the progression of disease in experimental model of glomerulonephritis.     

The effects of human and mouse pepsins on Masugi nephritis

The effects of intravenous administration of human or mouse pepsin were investigated on Masugi nephritis in rats and mice, which is an experimental model of glomerulonephritis in humans. Injection of anti-kidney serum to rats significantly increased the urinary protein excretion, serum levels of fibrinogen, cholesterol and immune complex, significantly decreased serum immunoglobulin G and complement levels, and caused histopathological changes such as detachment of endothelial cells from basement membrane, thickening of basement membrane, fusion of foot process and increase in hyaline cast in renal tubuli. Deposit of anti-rat IgG on glomerular capillary wall was also observed. All of these changes were ameliorated or showed a tendency to be ameliorated by intravenous administration of human pepsin, and the mechanism responsible for these effects was suggested to be selective decomposition of immune complex. Marked increase in urinary protein excretion was also observed in mice that intravenously received anti-kidney serum. This increase was suppressed by intravenous administration of human or mouse serum, the latter showing a stronger effect.     

The effects of azathioprine on experimentally induced immune complex renal disease in rabbits

To evaluate the effects of azathioprine on immune complex renal disease, soluble complexes of BSA-rabbit anti-BSA were injected into 5 groups of rabbits. Groups I, II and III received daily injections of azathioprine 1 mo prior to the administration of complexes. Group II continued to receive drug therapy for 1 subsequent mo. Groups IV and V received soluble complexes only. The groups were sacrificed at different intervals, and the kidneys were evaluated for morphologic and immunopathologic changes. Serologic and urinary protein studies were also done. No beneficial effects of therapy were noted on the development of glomerulonephritis in any experimental group. Continuous therapy appeared to have an adverse effect on the course of the glomerular lesions, with 44% of the continuously treated animals developing moderate disease as opposed to 5% of the pretreated and 7.1% of the control rabbits. The incidence of anaphylactic shock was diminished in the azathioprine treated animals. Immunohistologic localization of rabbit IgG was present in most animals, while B₁C was virtually absent. The presence of BSA was variable but notably absent in the long term azathioprine treated rabbits.     

Studies on antinephritic effect of mizoribine (p-INN, Bredinin), a new immunosuppressive agent, and azathioprine. (2) Effect on crescentic-type anti-GBM nephritis in rats

Crescentic-type nephritis was induced in rats by immunizing with rabbit gamma-globulin following i.v. injection of rabbit anti-rat glomerular basement membrane (anti-GBM) serum. The antinephritic effect of mizoribine was compared to that of azathioprine by administration from the 2nd day after the injection of anti-GBM serum to the 23rd day (Experiment I) and from the 15th to the 38th day (Experiment II). The experiment I assessment on the 24th day revealed that mizoribine at a dose of 7.5 mg/kg/day p.o. remarkably reduced plasma cholesterol level, wet kidney weight and glomerular histopathological changes (i.e., crescent formation and fibrinoid deposition). In addition, mizoribine at this dose also tended to reduce urinary protein excretion and the adhesion of capillary walls to Bowman's capsule. At a dose of 5 mg/kg/day p.o., mizoribine significantly reduced kidney weight and crescent formation. On the other hand, azathioprine at a dose of 20 mg/kg/day p.o. had a tendency to reduce these biochemical and histopathological parameters. In the experiment II assessment on the 39th day, the effects of both drugs were somewhat diminished compared to those in experiment I. Mizoribine strikingly inhibited the crescent formation with 5 and 7.5 mg/kg/day p.o. and inhibited the fibrinoid deposition with a dose of 7.5 mg/kg/day p.o. Azathioprine at a dose of 20 mg/kg/day p.o. was prone to reduce histopathological parameters. The above data indicate that mizoribine may be a useful new immunosuppressive agent for rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesion with the extensive formation of crescents.     

Studies on experimental immune complex nephritis (3). Therapeutic effect of prostaglandin E1 alpha-cyclodextrin host molecule (PGE1 . CD) on serum sickness nephritis in rats

The effect of prostaglandin E1 alpha-cyclodextrin host molecule (PGE1 . CD) was estimated by using a model of immune complex glomerulonephritis induced in rats by i.v. injection of 1 mg of rabbit serum albumin every other day. PGE1 . CD was given subcutaneously for 10 days after nephritis was definitely induced and resulted in a rapid restoration of various biochemical parameters, especially in plasma. The continuous s.c. administration of PGE1 . CD (300 micrograms/rat/day) with a mini osmotic pump provoked a therapeutic effect similar to that obtained with twice daily s.c. administration of PGE1 . CD (300 micrograms/rat X 2/day). Both PGE1 . CD groups revealed less glomerular damage and fewer locations of immune complexes in glomeruli as demonstrated by light and immunofluorescence microscopy. The beneficial effect of PGE1 . CD may be associated with reduced immune complex deposits in glomeruli. The present studies suggest that PGE1 . CD may enhance the clearance of immune complex deposits from the glomeruli rather than inhibiting the formation of immune complex in the circulation.     

Urinary transforming growth factor-beta 1 in various types of nephropathy.

Transforming growth factor-beta1 (TGF-beta1) is a potent multifunctional polypeptide that is involved in normal renal function and in the development of glomerular sclerosis. It is also an important mediator of the immune and anti-inflammatory responses.The purpose of this study was to examine whether the measurement of urinary TGF-beta1 excretion in patients with different types of renal diseases and in newly diagnosed type 1 diabetes mellitus represents a non-invasive tool to evaluate disease activity and to monitor response to therapy.We studied the urinary excretion of TGF-beta1 in 57 nephropathic patients divided in different groups according to the underlying disease: 15 had mesangial glomerulonephritis (IgAGN), 9 membranous glomerulonephritis (MGN), 7 rapidly progressive glomerulonephritis (RPGN), 8 systemic lupus erythematosus (SLE), 9 interstitial nephritis (IN), 9 chronic renal failure (CRF). TGF-beta1 was also measured in 38 patients with type 1 (insulin-dependent) diabetes mellitus (12 with newly diagnosed diabetes, 26 long-standing diabetes) and 31 healthy controls. Total urinary TGF-beta1 concentration was assayed by enzyme-linked immunoassay (ELISA), and expressed as a ratio to urinary creatinine concentration. The urinary TGF-beta1 levels were compared with the findings of biopsy and clinical parameters.Urinary TGF-beta1 excretion was significantly increased in all groups except MGN, IN and CRF. In non-diabetic patients, urinary TGF-beta1 levels correlated with crescent formation, floccular adhesion and mesangial proliferation, but not with the degree of tubulo-interstitial fibrosis. Urinary TGF-beta1 levels did not correlate with indices of renal function (serum creatinine, glomerular filtration rate (GFR), albumin excretion rate [AER]). Among diabetic patients, HbA(1C) significantly correlated with TGF-beta1 urinary excretion.Urinary TGF-beta1 levels may represent a valid indicator of acute glomerular flogosis associated with mesangial proliferation in glomerulonephrities. In newly diagnosed diabetic patients, hyperglycaemia seems to represent the principal factor leading to TGF-beta1 overproduction. Follow-up studies of urinary TGF-beta1 levels measured during optimal glycaemic control are necessary to clarify the relationship between hyperglycaemia and TGF-beta1 excretion.     

大鼠进行性被动性Heymann肾炎模型建立及其发病机制

目的 观察进行性被动性Heymann肾炎（ppHN）模型大鼠的肾损害并初步探讨其发病机制。方法 利用兔抗大鼠BBM抗血清多次免疫建立ppHN模型。检测实验第1、3、6、8周末24h尿蛋白、血清生化指标及超氧化物歧化酶（SOD）和丙二醛（MDA）水平,观察肾组织病理改变。结果 ppHN大鼠24h尿蛋白量进行性升高,血清SOD水平明显低于对照组,MDA水平明显高于对照组;肾脏病理改变为肾小球毛细血管基底膜增厚,上皮下免疫复合物沉积和足突融合。结论 ppHN是研究人类膜性肾病理想的动物模型,脂质过氧化损伤可能是导致肾损害的重要原因。     

Effect of selenium on blood pressure,urinary sodium excretion and plasma aldosterone in cadmium-treated male rats

The present study was carried out to help elucidate the possible mechanisms underlying the effect of Cd and the interaction of Se with Cd on blood pressure. Male Wistar rats were divided into four groups: control, Cd-treated, Se-treated, Se-and Cd-treated. Cd and Se were administered at doses of 1.0 mg/kg body weight by subcutaneous injection of aqueous solutions of CdCl₂·2×1/2 H₂O and Na₂SeO₃, respectively. Injections were made either alone or in the Cd+Se treated group, simultaneously at 12–h intervals for 7 consecutive days. All animals were then maintained without further treatment for an additional period of 18 days. Treatment with Cd and Se separately lowered the blood pressure on days 3 and 8, but these levels increased and were significantly higher than that in control rats by day 26. Plasma aldosterone concentrations increased and urinary Na excretion decreased from day 1 to 3 in rats treated with Cd and Se separately. Thereafter, increased water retention precedes the onset of increased blood pressure. From these findings, we suggest that in rats treated with Cd and Se separately the increase in plasma aldosterone is a main factor for decreased urinary Na excretion and increased retention of water, and these factors may be associated with an increase in blood pressure. The treatment with Cd and Se simultaneously decreased urinary Na excretion and increased the plasma aldosterone concentration and water retention before the onset of increased blood pressure. These findings suggest that the increase in the blood pressure in these rats might be the result of the same mechanisms as in the rats treated with Cd alone. Se administered simultaneously with Cd ameliorates the Cd-induced decrease in blood pressure on days 3 and 8 but did not ameliorate the Cd-induced increase in blood pressure on day 26. The Cd concentration in the serum of rats treated with Cd and Se simultaneously was markedly higher than that in the serum of rats treated with Cd alone on day 3, suggesting that a Cd–Se complex in serum would be formed. The effect of Se in preventing a Cd-induced decrease in blood pressure may be associated with the formation of a Cd-Se complex in the serum on day 3. On the other hand, after termination of treatment with Cd and Se there was no significant difference in the Cd concentrations in the serum between the rats treated with Cd alone and the rats treated with Cd and Se together. These findings suggest that a Cd–Se complex formed in serum on day 3 might be dissociated by day 26.     

The effects of Salvia przewalskii total phenolic acid extract on immune complex glomerulonephritis

Context: Salvia przewalskii Maxim. (Lamiaceae) is a Chinese herbal medicine that has long been used for the treatment of cardiovascular disease.

Objective: The study investigated the therapeutic efficacy of S. przewalskii total phenolic acid extract (SPE) on immune complex glomerulonephritis (ICG) in rats.

Materials and methods: Sixty-two Wistar rats were randomized into six groups. ICG was induced in all groups except normal control group. SPE was administered intragastrically at 24?h intervals for 40 consecutive days. Urine protein (UP), total serum protein (TSP), serum albumin (SA), serum cholesterol (SC) and serum urea nitrogen (SUN) were measured one day before, on day 20 and 40 after SPE administration. On day 40 after SPE administration, the kidneys were removed and prepared into pathologic sections. In addition, kidney wet mass was measured for calculating the kidney wet mass coefficient (KWMC).

Results: UP excretion was reduced significantly on day 20 after SPE administration in all three SPE groups as compared with that in medium group, and this effect was observable continuously until 40 days after SPE administration. Compared with medium group, TSP and SA were increased in all three SPE groups after 40 days treatment, while SC and SUN were decreased. KWMC was decreased significantly in 100?mg/kg SPE group after 40 days treatment compared with that in medium group. Histopathologic analyses showed that renal inflammatory infiltration and kidney intumesce were alleviated in all three SPE groups.

Conclusions: SPE may be a potential therapeutic drug for glomerulonephritis.     

Effects of glycyrrhetinic acid on aminonucleoside nephrosis in rats

The effects of glycyrrhetinic acid (GA), an aglycon of glycyrrhizin extracted from the roots of Glycyrrhizae radix, on puromycin aminonucleoside (PA) nephrosis were studied in rats. Urine protein excretion in female rats (130g–150g) receiving PA (50 mg/kg) alone was significantly elevated on the 2nd day after injection of PA and reached a peak on the 14th day. Urinary protein on the 14th day was reduced to 74% in animals treated with GA (20 mg/kg) starting on the 2nd day after injection of PA. The increase in serum cholesterol and the decrease in serum protein were also suppressed by GA. Observation by electron microscopy revealed that the degree of abnormality in glomerular epithelial cells, i.e. loss or fusion of foot processes, was lower in the rats treated with GA after PA injection than in the rat treated with PA alone. Moreover, pretreatment with GA did not suppress urinary protein excretion but when it was given at the same time as PA and after PA a significant decrease in urinary protein excretion was observed. Correspondence to: H. Abe at the above address     

Studies on antinephritic effect of TJ-8014, a new Japanese herbal medicine (3): Effects on crescentic-type anti-GBM nephritis in rats

We investigated the antinephritic effects of TJ-8014, in comparison to dipyridamole, on crescentic-type anti-GBM nephritis in rats. When administration of test drugs was started from the heterologous phase (from the day after the anti-GBM serum injection), TJ-8014 at 2.0 g/kg/day, p.o., markedly inhibited the urinary protein excretion and elevations of plasma cholesterol and urea nitrogen levels as well as glomerular histopathological changes (i.e., crescent formation, adhesion and fibrinoid necrosis) throughout the 40-day observation period. TJ-8014 at 0.1 and 0.5 g/kg/day, p.o., and dipyridamole at 0.4 g/day, p.o., inhibited only the histopathological changes. When treatment was started from the autologous phase (from the 22nd day after the anti-GBM serum injection) after the disease had been established, only the high dose of 5.0 g/kg/day of TJ-8014, p.o., was effective in improving the histopathological changes of the established nephritis, as assessed on the 53rd day. The low doses of TJ-8014 and dipyridamole were ineffective. These results suggest that TJ-8014 may be a useful Japanese herbal medicine against rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesions with the extensive formation of crescents. Furthermore, the mechanisms of action of this medicine will be discussed.     

Lack of a role for inducible nitric oxide synthase in an experimental model of nephrotic syndrome

Puromycin aminonucleoside (PAN) administration in rats produces an experimental model of nephrotic syndrome characterized by glomerular epithelial cell injury and proteinuria. The purpose of this study was to examine the role of nitric oxide (NO) in this model of minimal change glomerular disease. Aminoguanidine (AG) was used to inhibit inducible nitric oxide synthase (iNOS). Sprague-Dawley rats were divided into Control (N = 9), PAN (N = 14), AG (N = 2), and PAN + AG (N = 12) treatment groups. Control animals received saline (i.v. ), PAN animals received PAN (75 mg/kg, i.v.), and PAN + AG animals received PAN plus AG (50 mg/kg, i.p., twice daily). AG animals received a saline injection (i.v.) on day 0 in the place of PAN and then AG on the same schedule as the PAN + AG group. Animals were kept in metabolic cages, and urinary protein excretion and nitrite (NO(2)(-)) excretion were measured daily. PAN administration increased urinary NO(2)(-) excretion by day 2, and levels remained elevated through day 7. AG prevented this PAN-induced increase in urinary NO(2)(-) excretion. Plasma nitrate (NO(3)(-)) and NO(2)(-) (NOx) concentrations were also increased in the PAN and PAN + AG groups. iNOS protein expression was not detected in either the glomeruli or the cortex at day 7. Proteinuria developed in PAN animals on day 4 and increased steadily through day 7. PAN + AG animals showed a pattern similar to that of the PAN group. These results indicated that in contrast to models of proliferative glomerulonephritis, NO formation during PAN-induced nephrotic syndrome is increased but does not participate in the development of glomerular injury as measured by proteinuria.     

芪龙通肾方治疗膜性肾病大鼠蛋白尿的作用机制研究

目的观察芪龙通肾方治疗膜性肾病大鼠蛋白尿的疗效及作用机制。方法将SD大鼠随机分为空白,模型,阳性(雷公藤多苷片),芪龙通肾汤低、中、高剂量组,采用隔日1次尾静脉注射阳离子化牛血清白蛋白(C-BSA)方法复制膜性肾病大鼠模型,各组连续腹腔内注射治疗4周后检测大鼠尿蛋白定量(24 h)及血清指标[总蛋白(TP)、白蛋白(ALB)、血清总胆固醇(TC)、甘油三酯(TG)、尿素氮(BUN)、肌酐(Scr)、转化生长因子(TGF)-β1],采用光镜及电镜观察肾脏病理学改变。结果与模型组比较:阳性及芪龙通肾汤低、中、高剂量组尿蛋白定量(24 h)明显降低(P<0.05),且芪龙通肾汤中、高剂量明显低于阳性组(P<0.05);阳性及芪龙通肾汤高剂量组对血清TP、TC明显降低(P<0.05);阳性、芪龙通肾汤低、中、高剂量组对血清ALB明显升高、对TG和TGF-β1明显降低(P<0.05)。光镜及电镜观察,治疗组在肾小球基底膜免疫复合物沉积、基底膜增厚及足突融合等方面较模型组明显减轻。结论芪龙通肾方能有效降低膜性肾病大鼠蛋白尿,提高血清白蛋白,降低TGF-β1水平,减轻肾脏病理损伤。     

参麦、苯那普利综合治疗局灶节段性肾小球硬化的实验研究

目的：观察参麦注射液及苯那普利对大鼠局灶节段性肾小球硬化（FSGS）的治疗作用。方法：30只Wistar大鼠均分5组：（1）正常对照组（A组）；（2）参麦治疗组（B组）；（3）苯那普利治疗组（C组）；（4）综合治疗组（D组）；（5）模型组（E组）。采用小剂量分次阿霉素-间羟胺-高脂饲料法建立大鼠FSGS模型。B组、C组及D组于实验第29d分别予参麦注射液或苯那普利或参麦注射液 苯那普利治疗。测定24h尿蛋白、血生化指标、肾脏组织血流量、光镜及电镜检查。结果：（1）治疗后2周时各治疗组尿蛋白排泄量开始降低。实验12周时各治疗组胆固醇升高的幅度均低于模型组。（2）肾组织血流量测定：综合治疗组肾组织血流量明显增加。（3）光镜检查：肾小球硬化指数（SI）：综合治疗组明显降低。肾小球细胞外基质（ECM）/肾小球面积（GA）：各治疗组均明显减低。（4）电镜检查：综合治疗组毛细胞血管通畅，未见足突融合及炎症细胞浸润。结论：参麦、苯那普利综合治疗可起到多靶位协同治疗FSGS的良好疗效。     

茶多酚对家兔阳离子化牛血清白蛋白肾炎模型的治疗作用

目的 探讨茶多酚对家兔阳离子化牛血清白蛋白模型(C-BSA)肾炎的治疗作用. 方法 按文献方法复制家兔C-BSA肾小球肾炎模型,并用3种不同剂量的茶多酚 (30, 100 和 300 mg*kg-1) 给C-BSA肾小球肾炎模型兔灌胃,每日1次,连续 14 d. 结果 茶多酚不仅可以显著减少模型兔 24 h 尿蛋白分泌,降低血清肌酐和尿素氮水平,而且可以减轻肾小球病理损害,并且存在明显的量效关系. 结论 茶多酚对家兔C-BSA模型肾炎具有明显的治疗作用.     

Treatment of experimental nephrotic syndrome with artesunate

The present study was designed to test the therapeutic effect of a new antimalarial drug, artesunate in experimental model of nephrotic syndrome. To induce this experimental model, Adriamycin was given once by a single intravenous injection (7.5 mg/kg) through the tail vein. Six days after injection of Adriamycin, therapeutic protocol was developed by intraperitoneally (IP) administration of 5 mg/kg artesunate (ARS). Total of IP injections were 14, of which 5 injections were made every day and 9 injections were carried out at regular 48-h intervals. Therapeutic protocol was terminated on day 28 and animals were killed on day 49. The results showed that treatment with ARS caused a significant reduction in the level of proteinuria, urine urea and urine sodium compared with nontreated controls. In addition, decrease in serum triglyceride and increase in the level of serum albumin was significant in treated group with ARS compared with nontreated controls. Moreover, treatment with ARS significantly reduced glomerular polymorphonuclear (PMN) and mononuclear cells infiltration, hypercellularity, karyorrhexis, wire loops, and hydropic change in capillary network within the renal cortex, as well as decreased hyalin casts. On the other hand, healthy controls receiving ARS showed a significant decrease in amounts of serum triglyceride, urine urea, and urine sodium and potassium compared with normal group. These data suggest that artesunate therapy can ameliorate proteinuria, and suppress the progression of glomerular lesions in experimental model of nephrotic syndrome; it may also be recommended as a lipid-lowering drug.     

Effects of YM-13650 on experimental nephritis in rats and mice]

We investigated the effects of YM-13650, 2-(m-carboxyacetoxyphenyl) imidazo [2, 1-b] benzothiazole, on BSA-immune complex nephritis in rats and lupus nephritis in NZB/W F1 mice. In preventative experiments on immune complex nephritis in rats, YM-13650 (10 approximately 100 mg/kg, p.o.) dose-dependently inhibited the increase in urinary protein, serum cholesterol, and urea nitrogen. Histopathological observation showed striking hypercellularity and mesangial widening in nephritic control; however, glomerular injury was reduced in YM-13650-treated animals. In therapeutic study, control rats maintained high levels of urinary protein, serum cholesterol and urea nitrogen throughout the experimental period. These variables were lower in YM-13650-treated rats. In preventative experiments in lupus mice treated from 8 weeks of age, YM-13650 in comparison with the control group showed a lesser degree of proteinuria throughout the experimental period. It also significantly prolonged or tended to prolong the life span of NZB/W F1 mice compared with the control. In therapeutic experiments conducted after the onset of lupus nephritis in mice, the drug also inhibited an increase in urinary protein and tended to prolong the life span. These results show that YM-13650 has preventative and therapeutic effects on experimental nephritis in rats and mice, and it may prove valuable as an anti-nephritic drug.     

Studies on antinephritic effect of mizoribine (p-INN, Bredinin), a new immunosuppressive agent, and azathioprine (1) effect on the nephrotic type of anti-GBM nephritis in rats

The present study was made to investigate the antinephritic effect of mizoribine in comparison to that of azathioprine by using the nephrotic type of anti-rat glomerular basement membrane rabbit serum (anti-GBM serum)-induced nephritis in rats. The nephrotic type nephritis was induced in rats by two i.v. injections of anti-GBM serum at a 10 day interval. Both drugs were given orally, daily from the 2nd day following the first injection of anti-GBM serum to the 21st day. Mizoribine in doses of 5 and 7.5 mg/kg/day significantly inhibited urinary protein excretion by 30-40% on the 22nd day. Mizoribine at both doses showed an inhibitory tendency on urinary alkaline phosphatase (ALP) excretion on the 9th and 16th days. On the 22nd day, this drug at a dose of 7.5 mg/kg/day inhibited plasma cholesterol (CL) content by 59.6% and wet weight of kidneys by approx. 50%, but no significant difference was seen between the drug-treated and control groups. When renal tissues on the 22nd day were observed under light microscopy, mizoribine at both doses remarkably prevented glomerular changes such as mesangial proliferation and thickening of capillary walls and significantly inhibited the index of glomerular lesions (IGL) by over 60%. On the other hand, azathioprine at a dose of 20 mg/kg/day was as effective as mizoribine at 5 mg/kg/day in inhibiting urinary protein and ALP excretions, plasma CL content and kidney weight. However, azathioprine showed little effect on the IGL. From these results, mizoribine at the dose level of 1/4 to 1/3 of azathioprine showed a more potent effect than azathioprine in this model. Therefore, mizoribine is also expected to have a beneficial effect on nephrotic type nephritis in clinical fields.     

原发性肾小球病病人尿白蛋白与血浆胆固醇的关系

为探讨原发性肾小球病（ＰＧＤ）病人尿白蛋白与血浆胆固醇关系，对６３例诊断为肾病综合征和慢性肾炎病人的血胆固醇、白蛋白、尿白蛋白排泌进行测定与对比，结果显示，尿白蛋白排泌与血浆胆固醇呈正相关。