Crescentic-type anti-GBM Nephritis In Rats Research Articles

Contribution of ED-1- and CD-8-positive cells to the development of crescentic-type anti-GBM nephritis in rats.

The current studies were designed to identify which mononuclear leukocytes have an important role in the development of glomerular injury using rats with original-type (mild injury) and crescentic-type (severe injury) anti-glomerular basement membrane (GBM) nephritis. 1) Proteinuria was persistent in crescentic-type anti-GBM nephritis compared with original-type anti-GBM nephritis. Macrophages/monocytes (ED-1), cytotoxic/suppressor T cells (CD-8), interleukin-2-receptor (CD-25)-positive cells and Ia-positive cells accumulated remarkably and persisted for longer in crescentic-type nephritic glomeruli. 2) We then performed investigations using immunosuppressants. Cyclosporin A abrogated proteinuria more effectively than azathioprine in crescentic-type nephritis. However, plasma antibody titer and glomerular rat IgG deposition were equally reduced by both azathioprine and cyclosporin A. The increase in the numbers of ED-1-, CD-8- and CD-25-positive cells in nephritic glomeruli was completely inhibited by cyclosporin A, but inhibited only slightly by azathioprine. 3) There was a correlation between the degree of proteinuria and the number of ED-1- and CD-8-positive cells. It is likely that these cells are leukocytes that lead to glomerular injury in nephritis. 4) In additional experiments using monoclonal antibodies against macrophages/monocytes and cytotoxic/suppressor T cells, urinary protein excretion and accumulation of these cells were blunted in nephritic rats treated with these antibodies. These results suggest that ED-1- and CD-8-positive cells are involved in the development of crescentic-type anti-GBM nephritis.

Effect of DP-1904, a Thromboxane A2 Synthase Inhibitor, Administered from the Autologous Phase on Crescentic-Type Anti-GBM Nephritis in Rats

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane (TX) A2 synthase inhibitor, was compared with that of OKY-046 and azathioprine, using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane (GBM) nephritis. Test drugs were given p.o. once daily from an autologous phase in which proteinuria was already fully developed. DP-1904 (15 and 45 mg/kg per day) and OKY-046 (20 mg/kg per day), another TXA2 synthase inhibitor, significantly inhibited the development of glomerular alteration as well as the elevation of proteinuria. On the other hand, azathioprine (20 mg/kg per day), an immunosuppressive agent, failed to suppress the proteinuria. A single administration of DP-1904 or OKY-046 inhibited glomerular TXB2 production and increased glomerular prostaglandin (PG) E2 and 6-keto PGF1α production in nephritic rats. Both drugs apparently decreased the depositions of both rabbit immunoglobulin (Ig) G and rat IgG on GBM in nephritic rats, but azathioprine inhibited only the deposition of rat IgG. These results suggest that DP-1904 may be an effective agent for the treatment of proliferative glomerulonephritis and its antinephritic effect may be due to the amelioration of abnormal metabolism of arachidonic acid.

Acteoside, a Component of Stachys Sieboldii MIQ, May Be a Promising Antinephritic Agent: Effect of Acteoside on Crescentic-Type Anti-GBM Nephritis in Rats

Effects of acteoside (ACT) on crescentic-type anti-GBM nephritis in rats were investigated. When rats were treated with ACT from the 1st day after i.v. injection of anti-GBM serum, ACT inhibited the elevation of protein excretion into urine. In the ACT-treated rats, cholesterol and creatinine contents and antibody production against rabbit γ-globulin in the plasmas were lower than those of the nephritic control rats. Histological observation demonstrated that this agent suppressed hypercellularity and the incidence of crescent formation, adhesion of capillary wall to Bowman’s capsule and fibrinoid necrosis in the glomeruli. Furthermore, rat-IgG and C3 deposits on the GBM were significantly less in the ACT-treated group than in the control nephritic group. When the treatment was started from the 20th day after i.v. injection of anti-GBM serum, by which the disease had been established, ACT resulted in a similar effect on the nephritic rats as stated above. These results suggest that ACT may be a useful medicine against rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesions with diffuse crescents.

Acetoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent: effect of acteoside on crescentic-type anti-GBM nephritis in rats.

Effects of acetoside (ACT) on crescentic-type anti-GBM nephritis in rats were investigated. When rats were treated with ACT from the 1st day after i.v. injection of anti-GBM serum, ACT inhibited the elevation of protein excretion into urine. In the ACT-treated rats, cholesterol and creatinine contents and antibody production against rabbit gamma-globulin in the plasmas were lower than those of the nephritic control rats. Histological observation demonstrated that this agent suppressed hypercellularity and the incidence of crescent formation, adhesion of capillary wall to Bowman's capsule and fibrinoid necrosis in the glomeruli. Furthermore, rat-IgG and C3 deposits on the GBM were significantly less in the ACT-treated group than in the control nephritic group. When the treatment was started from the 20th day after i.v. injection of anti-GBM serum, by which the disease had been established, ACT resulted in a similar effect on the nephritic rats as stated above. These results suggest that ACT may be a useful medicine against rapidly progressive glomerulonephritis, which is characterized by severe glomerular lesions with diffuse crescents.

O-406 - Studies on antinephritic effect of TJC-160, a component of Stachys sieboldii MIQ (chorogi), on crescentic-type anti-GBM nephritis in rats.(1)

O-406 - Studies on antinephritic effect of TJC-160, a component of Stachys sieboldii MIQ (chorogi), on crescentic-type anti-GBM nephritis in rats.(1)

Studies on the Antinephritic Effects of Plant Components (6): Antinephritic Effects and Mechanisms of Phellodendrine (OB-5) on Crescentic-Type Anti-GBM Nephritis in Rats (2)

Effects of phellodendrine (OB-5) on crescentic-type anti-GBM nephritis in rats and the cell number of the various leukocyte subpopulations in the glomeruli of the nephritic rats were investigated. OB-5 at 25, 50 and 100 mg/kg/day, p.o. prevented the urinary protein excretion by the 19th day after i.v.-injection of anti-GBM serum. In the OB-5-treated rats, plasma cholesterol and creatinine contents were lower than those of the control rats throughout the 40-day experimental period. Histopathological observations demonstrated that OB-5 inhibited the incidence of crescent formation, adhesion and fibrinoid necrosis in the glomeruli by the 41st day. OB-5 did not affect the plasma antibody titer against rabbit gamma globulin. The increases in total leukocytes, macrophages, cytotoxic/suppressor T cells, la positive cells, and IL-2 receptor positive cells in the glomeruli in OB-5, 100 mg/kg-treated rats as well as those of the animals treated with azathioprine or cyclosporin A were lower than those of the anti-GBM nephritic control. These results indicate that OB-5 was effective in crescentic-type anti-GBM nephritis and the antinephritic mechanisms of this agent may be due to its ability to inhibit the proliferation or the migration of macrophages and cytotoxic T lymphocytes in the glomeruli.

Studies on the antinephritic effects of plant components (6): antinephritic effects and mechanisms of phellodendrine (OB-5) on crescentic-type anti-GBM nephritis in rats (2).

Effects of phellodendrine (OB-5) on crescentic-type anti-GBM nephritis in rats and the cell number of the various leukocyte subpopulations in the glomeruli of the nephritic rats were investigated. OB-5 at 25, 50 and 100 mg/kg/day, p.o. prevented the urinary protein excretion by the 19th day after i.v.-injection of anti-GBM serum. In the OB-5-treated rats, plasma cholesterol and creatinine contents were lower than those of the control rats throughout the 40-day experimental period. Histopathological observations demonstrated that OB-5 inhibited the incidence of crescent formation, adhesion and fibrinoid necrosis in the glomeruli by the 41st day. OB-5 did not affect the plasma antibody titer against rabbit gamma globulin. The increases in total leukocytes, macrophages, cytotoxic/suppressor T cells, Ia positive cells, and IL-2 receptor positive cells in the glomeruli in OB-5, 100 mg/kg-treated rats as well as those of the animals treated with azathioprine or cyclosporin A were lower than those of the anti-GBM nephritic control. These results indicate that OB-5 was effective in crescentic-type anti-GBM nephritis and the antinephritic mechanisms of this agent may be due to its ability to inhibit the proliferation or the migration of macrophages and cytotoxic T lymphocytes in the glomeruli.

Studies on anti-nephritic effects of plant components (5). Effects of pherodendrin on original and crescentic-type anti-GBM nephritis in rats

Effects of pherodendrin (OB-5) on anti-GBM nephritis were investigated. OB-5 (50 mg/kg/day, i.p.) prevented the urinary protein excretion in original and crescentic-type anti-GBM nephritis in rats. In addition, OB-5 also inhibited the elevation of serum creatinine, urea nitrogen and cholesterol contents in both models of nephritis. Histopathological observations indicated that OB-5 prevented the hypercellularity, crescent formation, adhesion and fibrinoid necrosis in the glomeruli of nephritic rats. OB-5 and cyclosporine A, a positive control drug, prevented the increase in the number of OX-1, CD8 and ED-1 positive cells in the glomeruli. These results indicated that OB-5 may be effective in human glomerulonephritis, and anti-nephritic mechanisms of OB-5 may be due to its inhibition of the activation of macrophages or cytotoxic T cells.

Lipo PGE1の抗腎炎効果に関する研究(1)ラットの半月体タイプ抗GBM腎炎に対する効果

Lipo PGE1の抗腎炎効果に関する研究(1)ラットの半月体タイプ抗GBM腎炎に対する効果

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.

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.

Antinephritic effects of PGE1 and thiaprostaglandin E1, TEI-5178 and TEI-6122, on crescentic-type anti-GBM nephritis in rats.

The antinephritic effects of PGE1, TEI-5178 and TEI-6122 on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats were investigated. The test compounds were subcutaneously administered every day for 39 days after the injection of anti-GBM serum. PGE1 (2.0 mg/kg/day), TEI-5178 (0.25 or 0.5 mg/kg/day) and TEI-6122 (0.25 or 0.5 mg/kg/day) significantly reduced urinary protein by 30 to 50% of that of the control at the late stage of nephritis. These test compounds also suppressed the increase of blood urea nitrogen and the development of alteration in the glomeruli by the 40th day. Both TEI-5178 (0.5 mg/kg/day) and TEI-6122 (0.5 mg/kg/day) significantly suppressed the production of antibody to rabbit gamma-globulin in nephritic rats. This was not the case with PGE1, however. In additional experiments to clarify the antinephritic mechanisms of the test compounds, it was found that 15 min after one subcutaneous injection of PGE1 (1.0 mg/kg), TEI-5178 (0.5 mg/kg) or TEI-6122 (0.5 mg/kg), systolic blood pressure in the nephritic rats was transiently reduced by 50 to 60%. On the other hand, these test compounds augmented renal blood flow (20-50%) from 45 min after the injection. The relationship between the antinephritic effect and these subsequent findings will be discussed.

Antinephritic effect of OKY-046, a thromboxane A synthetase inhibitor (1). Effects on crescentic-type anti-GBM nephritis in rats.

To induce crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis, male Sprague-Dawley rats were immunized with rabbit gamma-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. At the same time, original type anti-GBM nephritis was induced in other rats by anti-GBM serum only. The animals with crescentic-type anti-GBM nephritis showed significantly higher platelet aggregability than that in rats with original-type anti-GBM nephritis at days 5, 10 and 40 after anti-GBM serum administration, respectively. To estimate the antinephritic effect of OKY-046, a thromboxane A synthetase inhibitor, it was given orally to rats at doses of 0.5, 2.5 or 20 mg/kg for 39 days after anti-GBM serum. OKY-046 (20 mg/kg) significantly inhibited the increase in both urinary protein and plasma cholesterol levels (40% and 35% vs. control, respectively). Moreover, when examined by light microscopy, this drug remarkably prevented histological involvement of the glomeruli. OKY-046 at 20 mg/kg had suppressed the hyperaggregability of platelets by 77% by day 40 as compared with the control, but doses of 0.5 and 2.5 mg/kg did not. It is concluded from these data that OKY-046 has beneficial effects on crescentic-type anti-GBM nephritis and may act through inhibition of not only platelet TxA2 but also glomerular TxA2 in its action to prevent histological alterations.

Antinephritic effect of Y-19018, a thromboxane A synthetase inhibitor, on crescentic-type anti-GBM nephritis in rats.

In order to investigate the antinephritic effect of Y-19018, a thromboxane A synthetase inhibitor, on crescentic-type anti-glomerular basement membrane (anti-GBM) nephritis in rats, the present study was undertaken. Male Sprague Dawley rats were immunized with rabbit gamma-globulin in Freund's complete adjuvant following i.v. injection of anti-GBM serum. Y-19018 at a dose of 0.3 and 3.0 mg/kg was given orally to rats from the day after the injection of anti-GBM serum (day 1) to day 39. Y-19018, 3.0 mg/kg, significantly inhibited both urinary protein excretion (30.6%) on day 19 and plasma cholesterol (39.8%) on day 15. Moreover, light microscopy demonstrated that this drug at both doses remarkably prevented histological involvement of the glomeruli on day 40 in a dose-dependent manner. In the blood obtained from nephritic rats, platelet aggregation was increased. Y-19018 suppressed (48.7%) the hyperaggregability of platelets on day 40 at a high dose, although the suppression of platelet aggregation was not in a dose-dependent manner. It is concluded from these data that Y-19018 shows beneficial effects on crescentic-type anti-GBM nephritis and may exert its action partly through inhibition of glomerular TXA2.

Studies on Mechanisms of Antinephritic Action of SA-446, an Angiotensin I Converting Enzyme Inhibitor (1) A Comparison with Actions of Spironolactone, Kallidinogenase and Saralacin

The present study was made to clarify the mechanisms of the antinephritic action of SA-446, an angiotensin I converting enzyme inhibitor, on crescentic-type anti-GBM nephritis in rats as compared to the actions of spironolactone (an antialdosterone agent), kallidinogenase (a kallikrein agent) and saralasin (an angiotensin II antagonist). SA-446 (25 mg/kg/day, p.o.) had a tendency to reduce the urinary protein excretion and plasma urea nitrogen content. In addition, this drug remarkably inhibited not only glomerular histopathological changes (i.e., crescent formation, the adhesion of capillary walls to Bowman's capsule and fibrinoid necrosis) but also the elevation of blood pressure. Spironolactone (25 mg/kg/day, p.o.) and kallidinogenase (25 KU/day, i.m.) also showed beneficial effects on glomerular histopathological changes and hypertension, although both drugs were not as effective as SA-446. Flowever, saralasin (72 μg/day, s.c.) caused a marked aggravating action on this nephritis. This nephritic model showed a marked low activity of plasma renin all through the 40 day experimental period. In this model, the urinary aldosterone excretion was increased, in spite of the decrease in plasma renin activity. SA-446 and kallidinogenase significantly inhibited the decrease in plasma renin activity and the increase in urinary aldosterone excretion. Spironolactone inhibited only the increase in the aldosterone excretion. However, saralasin decreased the plasma renin activity under the control level and strongly increased the urinary aldosterone excretion (about 1.8 times the control level on the 20th day). These results suggest that the antinephritic effect of SA-446 may be related to the antihypertensive action and the increase in renal blood flow through activation of the kallikrein-kinin and prostaglandins systems.

ラットの半月体タイプ抗GBM腎炎に対する新angiotensin I変換酵素阻害剤,SA446[2R4R]-2-(o-hydroxypenyl)-3-(3-mercaptopropionyl)-4-thialzolidinecarboxylic acidの抗腎炎効果

ラットの半月体タイプ抗GBM腎炎に対する新angiotensin I変換酵素阻害剤,SA446[2R4R]-2-(o-hydroxypenyl)-3-(3-mercaptopropionyl)-4-thialzolidinecarboxylic acidの抗腎炎効果

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 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 r-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 1 5th 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 lesions with the extensive formation of crescents.