Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A newly developed immunosuppressive drug, FK506 (Fujisawa, Japan) is known to inhibit T-cell immunity. We have evaluated the action of this compound in MRL/lpr mice which develop a severe autoimmune disease. Eight-week-old female MRL/lpr of mice were treated subcutaneously with 2 mg/kg (high dose), 0.8 mg/kg (medium dose), 0.2 mg/kg (low dose) or solvent only (control) six times per week. Survival times of the mice were prolonged in the medium and the high dose treatment groups. The lymph node swelling was dramatically prevented with the high dose treatment. The increasing footpad swelling seemed to be also suppressed with the treatment. FACS analyses of the spleen cells revealed that FK506 reduced the percentage of double negative T cells (Thy-1.2+, Lyt-2-, L3T4-). Serological studies showed that anti-ssDNA and anti-dsDNA activities were significantly reduced by the high dose treatment, which is different from recent findings with Cyclosporine A. The high dose treatment also suppressed the total amount of IgG, even though the IgG concentration was rather increased by the medium dose treatment. Decreased proteinuria as well as pathological evaluations of the kidneys and lungs indicated that there were marked ameliorations in these organs with the treatment. These results suggest that FK506 could be potentially used for the treatment of autoimmune diseases.
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PMID:Experimental treatment of autoimmune MRL-lpr/lpr mice with immunosuppressive compound FK506. 168 94

Mesangial pathology is a hallmark of focal and segmental glomerulosclerosis (FGS). In an immunologically mediated mesangial cell (MC) injury model, we analyzed the relationship between mesangial hypercellularity, increased macromolecular uptake by the mesangium, and long-term pathologic sequelae. A single injection of monoclonal anti-Thy-1 (AT) antibody induces MC apoptosis, extensive mesangiolysis, proteinuria, MC proliferation, and hypercellularity. Immunohistologic analysis indicated influx of ED 1-positive macrophages after 24 hours, which gradually subsiding thereafter. At day 12, hypercellularity was due to smooth musclelike MCs, and macrophagelike MCs were absent. Injection of iron dextran in nephritic rats indicated that mesangial uptake of iron correlated with mesangial hypercellularity, but was independent of proteinuria. Long-term studies showed no difference after 19 weeks in FGS between nephritic and control rats. In conclusion, although mesangiolysis is accompanied by influx of macrophages, a phase of smooth musclelike MC proliferation and increased macromolecular uptake, these pathologic events do not result in chronic mesangial pathology and FGS.
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PMID:The mesangium in anti-Thy-1 nephritis. Influx of macrophages, mesangial cell hypercellularity, and macromolecular accumulation. 197 99

Intravenous administration of heterologous anti-rat thymocyte serum (ATS), which reacts with a Thy-1-like antigen present on rat glomerular mesangial cells, caused lytic (1 hr to 2 days), hypercellular (4 to 14 days), and sclerotic (2 to 3 months) mesangial lesions in Lewis rats. The normal control of 48.6 +/- 7.9 (mean +/- SD) glomerular nuclei on histologic section decreased significantly (P less than 0.001) to 39.8 +/- 6.1, 37.4 +/- 6.0, and 38.9 +/- 6.8 at one hour, four hours and two days after ATS administration, respectively. Thereafter glomerular nuclei increased to 54.7 +/- 11.5 (P less than 0.05) at four days, 62.5 +/- 9.6 (P less than 0.001) at one week and 64.1 +/- 14.2 (P less than 0.001) at two weeks, and normalized (P greater than 0.05) to 49.4 +/- 8.9 at one month and 50.6 +/- 9.0 at three months. By electron microscopy, glomerular damage in the lytic stage was restricted to mesangial cells and was manifested as hydropic degeneration or lysis. Rabbit IgG and rat C3 were found in the mesangium one hour after injection; they decreased at two days and were negligible at four days. By paired label isotope study, 11.6 micrograms of antibody bound per 7.6 X 10(4) glomeruli at one hour was needed to induce mesangial cell degeneration. No or only minimal changes in proteinuria and in serum creatinine were observed with the dosage used in this rat strain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat. 289 61

IgA nephropathy (IgAN) is a chronic form of glomerulonephritis (GN) characterized by the deposition in the glomerular mesangium of mainly IgA. An experimental form of mesangial proliferative GN can be induced in rats by either polyclonal or monoclonal antibodies against Thy-1.1, a glycoprotein present on the surface of MC. The IgG-mediated renal inflammation is complement dependent and associated with influx of platelets and monocytes. In the present study we switched an IgG2a anti-Thy-1.1 (ER4G) producing hybridoma to an IgA anti-Thy-1.1 (ER4A) producing clone and analyzed the effects of IgA anti-Thy-1.1 in rats. FPLC analysis by gel filtration revealed that the IgA produced by the hybridoma cells was mainly dimeric and polymeric. Infusion of rats with purified ER4A (1 mg/kg) resulted in the deposition of IgA in a mesangial pattern in the glomeruli, similar to that found with ER4G. While administration of ER4G resulted in proteinuria, no significant urinary protein excretion was found in rats treated with ER4A. However, significant microhematuria was observed in rats receiving either ER4A or ER4G. Furthermore, the administration of ER4A was not accompanied by activation of complement, and no significant influx of monocytes or polymorphonuclear leukocytes was observed in contrast to the rats receiving ER4G. We conclude that microhematuria is selectively induced in Wistar rats by mouse IgA anti-Thy-1.1 without detectable complement-mediated injury to MC. These studies may be of importance in understanding the mechanisms leading to IgAN in patients.
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PMID:Induction of microhematuria by an IgA isotype switch variant of a monoclonal anti-Thy-1.1 antibody in the rat. 891 28

We examined the functional role of interleukin (IL)-1 in mesangial cell proliferation during rat anti-Thy-1 nephritis by blocking its action with IL-1 receptor antagonist (IL-1ra). Anti-Thy-1 nephritis was induced by intravenous injection of 5 mg/kg OX-7 IgG (day 0) into inbred Wistar rats. Groups of animals (n = 9) were implanted with a micro-osmotic pump on day -1, which delivered 25 micrograms/hour human recombinant IL-1ra or saline continuously until the rats were killed at day 6, the peak of mesangial cell proliferation. Immunostaining showed that IL-1 was expressed by mesangial cells during disease. IL-1ra treatment did not affect the mild, but significant, proteinuria seen after OX-7 injection. Compared with saline treatment, IL-1ra treatment reduced mesangial cell proliferation (decreases 24% P < 0.05), glomerular hypercellularity (decreases 29%; P < 0.05), and glomerular macrophage accumulation (decreases 20%; P < 0.05). However, IL-1ra treatment had no effect on glomerular IL-1 beta mRNA expression and caused only a small reduction in the high levels of glomerular expression of platelet-derived growth factor-beta protein (decreases 6%; P < 0.05). IL-1ra caused a modest reduction in the marked up-regulation of glomerular transforming growth factor-beta 1 mRNA expression on day 6 (decreases 26%; P < 0.05), although urinary excretion of this factor was unaffected. Interestingly, IL-1ra treatment had relatively little effect upon glomerular deposition of laminin, fibronectin, and collagen type IV seen in this acute disease. In conclusion, this study has 1) demonstrated that IL-1 is expressed by mesangial cells in vivo, 2) demonstrated that IL-1 is a mesangial cell growth factor in experimental mesangioproliferative nephritis, and 3) suggests that IL-1 has little or no fibrogenic activity in mesangial matrix deposition.
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PMID:Role of interleukin-1 in mesangial cell proliferation and matrix deposition in experimental mesangioproliferative nephritis. 921 40

We previously reported a new animal model of progressive glomerulonephritis induced by a single intravenous injection of the anti-Thy-1 monoclonal antibody MoAb 1-22-3 into uninephrectomized rats (Clin Exp Immunol 102: 181-185, 1995). We examined the effects of angiotensin II (Ang II) receptor antagonist (candesartan) on the clinical features and morphological lesions of this new model. By 10 weeks after induction of nephritis, untreated rats had developed hypertension, massive proteinuria, renal dysfunction, and severe glomerular injury, while uninephrectomized control rats had not. There was a significant increase in levels of glomerular protein and cortical mRNA for transforming growth factor-beta (TGF-beta) and type I and type III collagens in untreated nephritic rats. Ten week treatments with candesartan and hydralazine significantly reduced blood pressure (BP) to an equal extent. Candesartan, but not hydralazine, prevented proteinuria, normalized renal function, and ameliorated glomerular injury. Candesartan also reduced levels of glomerular protein and cortical mRNA for TGF-beta and type I and type III collagens, while hydralazine did not. These findings suggest that candesartan prevents progression to end-stage renal failure by modulating the effects of Ang II at least in part on the production of TGF-beta and type I and type III collagens, and not merely on systemic BP.
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PMID:Candesartan prevents the progression of mesangioproliferative nephritis in rats. 940 66

Prostacyclin (PGI2) is known to have a relaxative action on vascular smooth muscle, an inhibitory action against platelet activation and neutrophil function. Previous studies showed the preventive effects of PGI2 on lupus nephritis and Thy-1 nephritis, although the mechanism has not been clarified. Glomerular endothelial expression of intercellular adhesion molecule-1 (ICAM-1) is up-regulated in experimental and human glomerular diseases, and is known to facilitate leukocyte infiltration into the glomeruli, which ultimately induces the various glomerular injuries. In the present study, we evaluated the therapeutic effects of PGI2 on a rat model for crescentic glomerulonephritis and investigated its putative mechanism in relation to ICAM-1-mediated leukocyte recruitment. Wistar-Kyoto (WKY) rats were injected with nephrotoxic serum and received continuous intraperitoneal infusion of PGI2. PGI2 dramatically decreased proteinuria (123.0 +/- 18.8 vs. 31.6 +/- 4.5), crescent formation and deposition of fibrinogen in the glomeruli, while the deposition of rabbit IgG, rat IgG and rat C3 along the capillary walls was not changed. Furthermore, intraglomerular expression of ICAM-1 and infiltration of macrophages were significantly suppressed by administration with PGI2. In contrast, influx of CD4 or CD8 positive cells was not altered. The present results suggest that PGI2 shows the preventive effects on experimental crescentic glomerulonephritis by inhibiting intraglomerular coagulation and ICAM-1-mediated macrophage-glomerular endothelial cell adhesive pathway.
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PMID:Therapeutic effects of prostacyclin analog on crescentic glomerulonephritis of rat. 957 47

The effects of chitosan-coated dialdehyde cellulose (chitosan DAC), a newly developed oral adsorbent for urea and ammonia, were examined in a glomerulonephritis model in rats. Mesangial proliferative glomerulonephritis accompanied with proteinuria was induced by an intravenous injection of anti-rat Thy-1.1 monoclonal antibody (OX-7). The proliferation of mesangial cells and an accumulation of extracellular matrix components such as type I collagen and fibronectin were observed in the glomeruli 9 days after OX-7 injection; these were improved in rats fed a diet containing chitosan DAC (10% content) for 9 days compared with those in rats fed a normal diet. Chitosan DAC treatment decreased the elevated urinary protein and blood urea nitrogen at days 8-9 to the normal levels; the increased fecal excretion of nitrogen might participate in this phenomenon. In addition, chitosan DAC treatment showed an increase in fecal water content associated with a decrease in urinary volume. These therapeutic effects may be due to the reduction of proteinic factor expression and the compensational function of chitosan DAC for kidney. These results suggest that chitosan DAC treatment may be useful for ameliorating mesangial proliferative glomerulonephritis.
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PMID:Effects of chitosan-coated dialdehyde cellulose, a newly developed oral adsorbent, on glomerulonephritis induced by anti-Thy-1 antibody in rats. 957 70

The pathophysiological role of the Thy-1.1 molecule expressed on rat mesangial cells with regard to mesangial cell dysfunction and injury remains unknown. The mechanism of Thy-1.1-associated injury has now been investigated with two monoclonal antibodies, 1-22-3 and OX7, that recognize different epitopes of Thy-1.1. Mesangiolysis and mesangial cell proliferation were more marked in rats injected with 1-22-3 than in those treated with OX7. Immunostaining for rat complement component C3 and also C9 was similar in the kidneys of rats 1 h after injection of either antibody. Alpha smooth muscle actin was first detected 3 days after injection of 1-22-3 and peaked on day 5; type I collagen staining showed a mesangial pattern on days 5 and 10. The staining for alpha smooth muscle actin and type I collagen was less intense in OX7-treated rats than in the 1-22-3-injected rats. The amounts of mRNAs encoding collagen types I and III peaked 5 days after injection of 1-22-3 and 10 days after injection of OX7. Rats injected with 1-22-3 developed proteinuria that was already marked on day 1 and peaked at 150 mg/day on day 3, whereas OX7 induced a low grade of proteinuria with large interindividual variability on day 3. Immunostaining for rat C3 in the normal rat kidneys, incubated in vitro with 1-22-3 or OX7 followed by incubation with normal rat fresh serum as a complement source, as well as the levels of serum complement activity, CH50, 30 min after injection of 1-22-3 or OX7 were similar, suggesting that the difference in the nephritogenicity of these two antibodies is not attributable to a difference in their complement-fixing activities, but rather may result from the difference in epitope specificities. The epitope recognized by 1-22-3 thus appears to be important in the initiation and progression of antibody-induced nephritis.
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PMID:Comparative nephritogenicity of two monoclonal antibodies that recognize different epitopes of rat Thy-1.1 molecule. 957 72

Multiple injections with a mouse monoclonal anti-rat Thy-1 antibody (five times, at weekly intervals) induced marked glomerular sclerotic lesions which are characterized by adhesion of glomerular capillaries to Bowman's capsule and persistent proteinuria in rats. Abnormal production of type I collagen and increased accumulation of type IV collagen and fibronectin were observed in these glomeruli. The glomerular expression of mRNA for these matrix components and transforming growth factor-beta1 (TGF-beta1) were markedly increased at 4 days after the last injections with anti-Thy-1 antibody, but decreased to below the levels of control rats at 5 weeks. This may be down-regulation of mRNA in mesangial cells. The glomerular sclerotic lesions were not progressive but the process of glomerular healing seemed to be retarded. The proteinuria and the glomerular adhesion were irreversible.
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PMID:Long-term observation of glomerulonephritis induced by multiple injections with anti-Thy-1 antibody in rats. 970 Oct 10


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