Biomedical subjects

T Nagamatsu

Publications and source records attributed to T Nagamatsu.

At least 19 recordsLinked to original sources

PubMed2001

Thromboxane A(2) causes retarded clearance of aggregated protein in glomeruli of nephritic mice.

Recently, it has been demonstrated that the production of prostaglandins and thromboxane is increased in patients with chronic glomerulonephritis and lupus nephritis. We recently demonstrated that thromboxane A(2) delayed the clearance of heat-aggregated bovine serum albumin deposited in glomeruli. In the present study, we investigated the effect of thromboxane A(2) on the clearance of macromolecules in nephritic glomeruli. First, we attempted to clarify the conditions for the clearance of heat-aggregated bovine serum albumin in nephritic glomeruli, using glomeruli isolated from control and anti-glomerular basement membrane nephritic mice. Heat-aggregated bovine serum albumin was injected twice into each mouse. The glomeruli were then isolated and incubated in culture medium. The heat-aggregated bovine serum albumin content of control glomeruli gradually diminished with incubation time up to 24 h. The heat-aggregated bovine serum albumin content of nephritic glomeruli was 69% higher than that of control glomeruli at 24 h incubation. The production of thromboxane B(2) (the stable metabolite of thromboxane A(2)) in nephritic glomeruli showed about a sevenfold increase compared with control. DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid hydrochloride], a thromboxane A(2) synthase inhibitor, and KT2-962 [sodium 3-(4-(4-chlorophenyl-butylsulfonamido) butyl)-6-isopropylazulene-1-sulfonate], a selective thromboxane A(2) receptor antagonist, significantly reduced the heat-aggregated bovine serum albumin content in nephritic glomeruli. Normal glomeruli treated with U-46619 [15S-hydroxy-11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid], a stable analogue of thromboxane A(2), had significantly more heat-aggregated bovine serum albumin than control glomeruli. We next investigated whether thromboxane A(2) could affect the uptake/disposal of heat-aggregated bovine serum albumin by cultured rat mesangial cells. U-46619 significantly enhanced the uptake and inhibited the disposal of heat-aggregated bovine serum albumin by mesangial cells. Finally, we performed experiments to elucidate the role of the thromboxane A(2) receptor (TP receptor) in the clearance of heat-aggregated bovine serum albumin using TP-deficient mice. The glomerular heat-aggregated bovine serum albumin content of TP-receptor knockout [TP(-/-)] mice was lower than that of wild-type [WT(+/+)] mice. U-46619 dose dependently increased the uptake of heat-aggregated bovine serum albumin by mesangial cells in WT(+/+) mice, but not in the TP(-/-) mice. These findings suggest that thromboxane A(2) retards the clearance of aggregated protein in nephritic glomeruli and may contribute to the pathophysiology of glomerulonephritis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Involvement of prostaglandin E2 in clearance of aggregated protein via protein kinase A in glomeruli.

Recently we immunohistochemically demonstrated that prostaglandin E2 (PGE2) promoted the clearance of aggregated bovine serum albumin (a-BSA) deposited in glomeruli. Herein, we investigated the role of PGE2 and its signal transduction in the disposal of macromolecules in glomeruli. EP2 and EP4 receptor mRNA was detected in glomeruli by RT-PCR analysis. A-BSA was injected twice into mice. Glomeruli were then isolated and incubated. A-BSA gradually disappeared from isolated glomeruli. PGE2 increased the intracellular cyclic AMP and decreased a-BSA level in glomeruli. Additionally, 8-bromocyclic AMP evoked a loss of a-BSA in isolated glomeruli. The effect of 8-bromo-cyclic AMP on the clearance of a-BSA was abolished by KT 5720 in glomeruli. PGE2 and 8-bromo-cyclic AMP also prompted disposal of a-BSA in cultured mesangial cells. These findings indicate that PGE2 positively regulates the removal of macromolecules via cyclic AMP and protein kinase A in glomeruli, and they provide insight into how to prevent the development of glomerulonephritis and glomerulosclerosis.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2000

Experimental incineration of low level radioactive samples.

To determine the volume reduction potential for incineration of radioactivity in low-level radioactive waste, an incineration experiment was performed at the Okayama University Radioisotope Center (OURIC). Solid low-level radioactive samples (LLRS) were prepared for 15 routinely used radionuclides (45Ca, 1251, 32p, 33p, 35S, 59Fe, 123I, 131I, 67Ga, 99mTc, 111In, 3H, 14C, 51Cr, and 201Tl). For each radionuclide, incinerated one at a time, the smoke duct radioisotope concentration was less than 1/10 of the regulatory concentration limit (The Japanese law concerning prevention of radiation hazard due to radioisotopes, etc.). The radionuclide-containing combustible and semi-combustible LLRS were incinerated at the AP-1 50R furnace erected at OURIC, and the distribution of radioactivity inside and outside the furnace was measured. In the experimental incineration of LLRS containing these 15 radionuclides, the fractions released (RF) in the gas phase of the final smoke duct ranged from 0.165 to 0.99. The radioactivities remaining in the incineration residue were 99mTc, 87%; 59Fe, 83.1%; 45Ca, 75%; 51Cr, 62.1%; 33P, 62.0%; 32P, 61.1%; 67Ga, 57.7%; 35S, 26.0%; 111In, 21.1%; 201Tl, 16.6%; 123I, 11.9%; 131I, 8.2%; 125I, 2.4%; 14C, 0.39%; 3H, 0.04%. In the incineration of LLR S containing 35S, the rate of adhesion to the furnace wall was lower at high-temperature (809 degrees C) incineration than at low-temperature (376 degrees C) incineration. For LLRS containing one of the three radioiodines, 123I, 125I, or 131I, no such difference was observed between low (372 degrees C) and high (827 degrees C) temperature incineration (RF varied from 0.82 to 0.94).

Incineration↗

PubMed2000

Molecular characterization of a novel yeast cell-wall acid phosphatase cloned from Kluyveromyces marxianus.

A novel Kluyveromyces marxianus gene that encodes an acid phosphatase, Pho610, was cloned in Saccharomyces cerevisiae. The deduced amino acid sequence was distinct from S. cerevisiae phosphatases but similar to some fungal enzymes. A peculiar feature of the sequence is that it has hydrophobic stretches both at the N- and C-termini, which is a characteristic of the precursors of glycosylphosphatidylinositol(GPI)-anchored proteins. When the gene was expressed in S. cerevisiae, the active enzyme was recovered in the periplasmic fraction by glucanase digestion. The Pho610 polypeptide was highly glycosylated and a significant portion was covalently linked to the cell-wall glucan. The enzyme was secreted when the C-terminal region was truncated to remove the GPI signal. Therefore, Pho610 is a novel cell-wall protein having an enzyme activity.

Acid Phosphatase↗

PubMed1999

Angiotensin II type I receptor antagonist suppresses proteinuria and glomerular lesions in experimental nephritis.

Angiotensin-converting enzyme inhibitors exert a beneficial effect on nephritis. We investigated the effects of KD3-671, an angiotensin AT1 receptor antagonist (2-propyl-8-oxo-1-[(2'-(H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-t etrahydro-cycloheptimidazole), on anti-glomerular basement membrane antibody-associated nephritis in rats. Untreated nephritic rats had massive proteinuria, glomerular lesions including crescent formation, a significant augmentation of proliferating cell nuclear antigen-positive cells, alpha-smooth muscle actin-positive cells, and the increase in deposition of proteoglycan, fibronectin and desmin in the glomeruli. Administration of KD3-671 to nephritic rats prevented the development of intense proteinuria, glomerular alterations and the increase in plasma urea nitrogen. KD3-671 suppressed the deposition of matrix protein and the expression of alpha-smooth muscle actin and desmin in the nephritic glomeruli. Captopril, an angiotensin-converting enzyme inhibitor, suppressed urinary protein excretion and the expression of desmin in the nephritic glomeruli, but not other parameters. These results suggest that KD3-671 may be a useful medicine against glomerulonephritis and glomerulosclerosis.

Angiotensin Receptor Antagonists↗

PubMed1999

Functional imaging in schizencephaly using [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and single photon emission computed tomography with technetium-99m-hexamethyl-propyleneamine oxime (HMPAO-SPECT).

We analyzed interictal [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FGD-PET) and single photon emission computed tomography with technetium-99m-hexamethyl-propyleneamine oxime (HMPAO-SPECT) in a 23-year-old female with schizencephaly. She had epilepsy and mild left hemiparesis, but was otherwise developmentally normal. We found the glucose metabolism and perfusion of the wall of the schizencephalic cleft to be identical to those of normal cerebral cortex. The wall of the transcerebral clefts, which were observed to be lined by abnormally organized gray matter as a result of a migration disorder, demonstrated gray matter metabolic activity and perfusion. FDG-PET and HMPAO-SPECT were thus found to be a useful complement to magnetic resonance imaging for evaluating schizencephaly.

Adult↗

PubMed1999

[Schizencephaly: clinical and MRI features].

We report the clinical and neuroimaging features of 4 cases with schizencephaly. Case 1 had bilateral schizencephaly with open-lip on the right and closed-lip on the left. Case 2 had unilateral schizencephaly with closed-lip on the left and subcortical heterotopia on the right. Case 3 had unilateral schizencephaly with closed-lip on the left. Case 4 had bilateral closed-lip schizencephaly. Although all cases except for Case 3 had bilateral lesions, neurodevelopmental outcome was generally good; Case 1 and 3 had mild hemiparesis. All patient have epilepsy which are well-controlled with antiepileptic drugs. Thus, the clinical presentation of schizencephaly, even if bilateral lesions, are quite variable.

Adolescent↗

PubMed1998

Effect of lipo-prostaglandin E1 on crescentic-type anti-glomerular basement membrane nephritis in rats.

The antinephritic effect of lipo-prostaglandin E1, prostaglandin E1 ((1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopent ane heptanoic acid) incorporated in lipid microspheres was investigated using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Lipo-prostaglandin E1 was given i.v. twice a day at 20, 40 and 80 microg/kg and azathioprine, an immunosuppressive agent, at 20 mg/kg was given p.o. once daily from the autologous phase, in which glomerulonephritis was fully developed (the 21 st day after injection of the anti-glomerular basement membrane serum), to the 50th day. Lipo-prostaglandin E1 (40 and 80 microg/kg x 2 per day) significantly inhibited the development of glomerular alterations as well as the elevation of proteinuria and plasma creatinine. Lipo-prostaglandin E1 (20 microg/kg x 2 per day) and azathioprine (20 mg/kg per day) significantly inhibited only the glomerular histopathological changes. Lipo-prostaglandin E1 at three doses significantly decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on the glomerular basement membrane in nephritic rats, but azathioprine apparently inhibited only the deposition of rat immunoglobulin G. A single administration of lipo-prostaglandin E1 inhibited the elevation of platelet aggregation and restored the decrease in renal tissue blood flow in nephritic rats. In addition, a single administration of lipo-prostaglandin E1 inhibited the elevation of glomerular thromboxane B2 and 6-keto prostaglandin F1alpha production in nephritic rats. These results suggest that lipo-prostaglandin E1 may be an effective agent for the treatment of glomerulonephritis. Its antinephritic effect may be due to the inhibition of platelet aggregation, an increase in renal tissue blood flow, a decrease in rabbit and rat immunoglobulin G deposition, and amelioration of the abnormal metabolism of arachidonic acid.

6-Ketoprostaglandin F1 alpha↗

PubMed1998

[Functional fitness and related factors in community-dwelling elderly].

To examine the association of level of functional fitness to demographic, health, and life behavioral or social factors, cross sectional data were obtained for 737 persons aged 60 years or older, and who were independently living in the community. Functional fitness was measured with a functional fitness test containing 4 task items: standing, walking, hand performance, and self-care performance. Among the demographic factors, statistically significant associations with functional fitness were found for age in both male and female and for the presence of spouse in male. Health status, previous or present history of circulatory diseases and musculo-skeletal diseases were significantly associated with lower levels of functional fitness in male, and previous or present history of musculo-skeletal diseases and presence of higher obesity associated with lower fitness level in female. With life behaviors, men who had habitual exercise activities and women who had no habitual nap but habitual exercise activities and frequent out-of-home activities showed significantly higher fitness level than their counterparts. These results suggest that level of functional fitness in independently living aged people in the community was significantly associated with the presence of spouse, history of circulatory and musculo-skeletal diseases, and habitual exercise activities in males; and with the history of musculo-skeletal diseases, obesity, and habitual exercise activities, napping, and frequent out-of-home activities in females.

Activities of Daily Living↗

PubMed1997

Modulation of anti-glomerular basement membrane nephritis in rats by ONO-1301, a non-prostanoid prostaglandin I2 mimetic compound with inhibitory activity against thromboxane A2 synthase.

The antinephritic effects of ONO-1301 ([7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]-aminooxy]ethyl]-1 -naphtyloxy]acetic acid) on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats were investigated. ONO-1301 was orally given to crescentic-type anti-GBM nephritic rats for 40 days after the induction of nephritis. ONO-1301 (30 mg/kg) suppressed the elevation of protein excretion into urine. In the ONO-1301-treated rats, cholesterol and urea nitrogen content in the plasma was lower than that of the nephritic control rats. Histological observation demonstrated that ONO-1301 suppressed the incidence of crescent formation and adhesion of capillary wall to Bowman's capsule. However, ONO-1301 failed to inhibit the antibody production against rabbit IgG and the rat-IgG deposition on the GBM. The increase in very late antigen-4 (CD49b, VLA-4)-positive cells in nephritic glomeruli was significantly reduced by ONO-1301 treatment on day 5. cAMP-elevating agents inhibited the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression on the surface of human umbilical vein endothelial cells (HUVECs) mediated by tumor necrosis factor (TNF)-alpha. These findings suggest that the antinephritic action of ONO-1301 is due to, at least in part, inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of VCAM-1.

Animals↗

PubMed1997

Thromboxane A2 interferes with a disposal process of aggregated protein in glomeruli.

Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were undertaken to determine if thromboxane A2 (TXA2) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumulated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA2, prostaglandin E2 (PGE2) and prostaglandin I2 concomitantly increased with the decrease of a-BSA in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly increased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA2 synthase inhibitors decreased TXA2 production in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists did not influence the generation of PGE2. The TXA2 analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA2 interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA2 may be an effective intervention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase.

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.

Animals↗

PubMed1996

Butein (3,4,2',4'-tetrahydroxychalcone) ameliorates experimental anti-glomerular basement membrane antibody-associated glomerulonephritis (3).

The antinephritic effects of butein (3,4,2',4'-tetrahydroxychalcone) on original-type anti-glomerular basement membrane antibody-associated glomerulonephritis in rats were investigated. Butein was given to anti-glomerular basement membrane antibody-associated glomerulonephritic rats for 15 days after the induction of nephritis. Butein prevented proteinuria and histological alterations. The up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression and increase in leukocyte function-associated antigen-1 (LFA-1) positive cells in nephritic glomeruli significantly declined with butein treatment. In the further investigation to clarify the effects of butein on ICAM-1 expression, human umbilical vein endothelial cells were treated with butein in the presence of tumor necrosis factor-alpha (TNF-alpha) or phorbol 12-myristate 13-acetate (PMA). Butein prevented the up-regulation of ICAM-1 expression mediated by TNF-alpha or PMA on human umbilical vein endothelial cells in a dose-dependent manner. When human umbilical vein endothelial cells or neutrophils were treated with butein, the adhesion of neutrophils to human umbilical vein endothelial cells was suppressed. These data suggest that the antinephritic action of butein is due to inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of ICAM-1 and the inhibition of a function of adhesion molecules on the surface of leukocytes.

Animals↗

PubMed1996

Effect of DP-1904, a thromboxane A2 synthase inhibitor, on passive Heymann nephritis in rats.

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A2 synthase inhibitor, was evaluated using an experimental model of membranous nephropathy, viz. accelerated passive Heymann nephritis in which the glomerular injury is mediated by immune complexes. DP-1904 markedly inhibited the develop-ent of glomerular alteration as well as the elevation of proteinuria and plasma creatinine. When the treatment was started from the 22nd day, at which time proteinuria is fully developed, DP-1904 showed beneficial effects on proteinuria and glomerular histopathological changes. DP-1904 apparently decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on glomerular basement membrane in nephritic rats. A single administration of DP-1904 restored the decreased renal tissue blood flow, inhibited glomerular thromboxane B2 production and increased glomerular prostaglandin E2 and 6-keto prostaglandin F1 alpha production in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of idiopathic membranous nephropathy and that the beneficial effect of this drug may be due to the elimination of glomerular immune deposits and to an increase in renal tissue blood flow related to amelioration of the abnormal metabolism of arachidonic acid.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Expression of a nonmuscle myosin heavy chain in glomerular cells differentiates various types of glomerular disease in rats.

To characterize the phenotypic modulation of mesangial and glomerular epithelial cells, we investigated the expression of a nonmuscle type myosin heavy chain, SMemb, and alpha-smooth muscle actin (alpha-SM actin) in rat experimental glomerular diseases, which included anti-Thy 1 nephritis, 5/6 nephrectomy, diabetes, and anti-glomerular basement membrane nephritis. SMemb was only slightly expressed in normal glomerular epithelial cells but not in mesangial cells. In the anti-Thy 1 nephritis rats, both SMemb and alpha-SM actin were most conspicuously induced in mesangial cells. However, the expression profile was shifted from alpha-SM actin to SMemb dominant pattern over the course of glomerulonephritis. The expression of SMemb was also increased in epithelial cells in this model. In the other three models, glomerular cells did not express alpha-SM actin, but did so for SMemb. In the nephrectomized and the diabetic rats SMemb was newly expressed in mesangial cells at earlier stages, but at later stages was remarkably enhanced in epithelial cells when severe glomerular hypertrophy developed. In the anti-GBM nephritis rats, SMemb expression was increased in epithelial cells. In all models examined, mesangial and epithelial expression of SMemb was confirmed by immunoelectron microscopy, and enhanced expression of SMemb mRNA in glomeruli was verified by RNase protection assay. We conclude from these results that glomerular cells change their phenotypes differently depending on various types of glomerular diseases. These phenotypic changes in glomerular cells can be revealed by the combined immunostaining for SMemb and alpha-SM actin. SMemb is especially useful to detect both mesangial and glomerular epithelial cell activation in these glomerular disease models. Understanding the functional difference and regulatory mechanisms of these cytoskeletal proteins will provide insight into the pathogenesis and progression of glomerular diseases.

Actins↗

PubMed1996

Acteoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent (3): effect of aceteoside on expression of intercellular adhesion molecule-1 in experimental nephritic glomeruli in rats and cultured endothelial cells.

It is known that adhesion molecules play a crucial role in the development of glomerulonephritis. Therefore, we investigated the effects of acteoside on the expression of intercellular adhesion molecule-1 (ICAM-1) in nephritic glomeruli, in vivo, and human umbilical vein endothelial cells (HUVECs) and rat mesangial cells, in vitro. Aceteoside treatment significantly decreased the up-regulation of ICAM-1 expression in nephritic glomeruli. Acteoside prevented the up-regulation of ICAM-1 expression mediated by inflammatory cytokines or phorbol 12-myristate 13-acetate on HUVECs and rat mesangial cells. Adhesion of neutrophils and macrophages to acteoside-treated HUVECs was suppressed to one half of that in untreated HUVECs. These data support the finding that acteoside inhibits the up-regulation of ICAM-1 in the nephritic glomeruli. Additionally, it is suggested that the antinephritic action of acteoside is due to the inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of ICAM-1. This is the first paper demonstrating that the up-regulation of ICAM-1 in nephritic glomeruli is inhibited by a natural product, acteoside.

Animals↗

PubMed1996

The possible roles of hyperlipidemia and mononuclear cells in glomeruli in puromycin aminonucleoside nephrosis in rats.

The possibility that hyperlipidemia and an increase of mononuclear cells in the glomeruli could participate in the pathogenesis of minimal change glomerulopathy was evaluated in puromycin aminonucleoside (PAN) nephrosis in rats. Significant increases in intraglomerular CD4-, IL-2-receptor (R)- and ED-1-positive cells were found in PAN rats. Urinary protein excretion and mononuclear cells in the glomeruli of 1% cholesterol diet-fed rats significantly increased, compared with standard diet feeding. Moreover, administration of a subnephrogenic dose of PAN in cholesterol diet-fed rats substantially increased urinary protein excretion and mononuclear cells in the glomeruli. Additionally, antihyperlipidemia agents and immunosuppressive agents prevented urinary protein excretion and increases of CD4-, IL-2R- and ED-1-positive cells in the glomeruli of PAN nephrotic rats. Monoclonal antibodies directed against these cells also prevented urinary protein excretion. These results suggest that CD4-, IL-2R- and ED-1-positive cells and hyperlipidemia are involved in the progression, but not the pathogenesis, of PAN.

Animals↗

PubMed1996

Suppression of experimental crescentic-type anti-glomerular basement membrane (GBM) nephritis by FK506 (tacrolimus hydrate) in rats.

The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Streptomyces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-positive cells and intercellular adhesion molecule-1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-alpha. On the other hand, IL-2 production from the spleen cells isolated from nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.

Animals↗