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)

The role of the beta 2 integrin cell adhesion molecules (CAM) in directing neutrophil accumulation and injury in acute anti-glomerular basement membrane antibody induced glomerulonephritis (anti-GBM GN) was assessed in rabbits by in vivo inhibition of CD18 dependent neutrophil/endothelial cell interactions using a monoclonal anti-CD18 antibody. Rabbits given horse anti-rabbit GBM antibody developed significant glomerular neutrophil influx (2.9 +/- 0.1 neutrophils per glomerular cross-section [c/gcs], normal 0.1 +/- 0.1 c/gcs, P = 0.002) and proteinuria (1389 +/- 257 mg/16 h, normal 15 +/- 4 mg/16 h, P = 0.0015) after 16 h. Rabbits rendered neutropenic (< 500 neutrophils/microL) by mustine hydrochloride, or complement depleted by cobra venom factor, did not develop glomerular neutrophil accumulation and had markedly reduced proteinuria after anti-GBM antibody, demonstrating complement-induced neutrophil recruitment is a major mechanism of glomerular injury in this model. Anti-CD18 antibody treatment of rabbits developing anti-GBM GN abrogated dermal neutrophil influx in response to intradermal injection of fMLP and zymosan activated serum. Treated rabbits achieved levels of anti-CD18 antibody in their serum which saturated the binding sites on rabbit neutrophils in vitro, and their circulating neutrophils had saturated anti-CD18 antibody binding in vivo. However, glomerular neutrophil influx (3.5 +/- 0.4 c/gcs) and proteinuria (1210 +/- 428 mg/16 h) were both unaffected. Thus, in this model of antibody-initiated complement and neutrophil-dependent glomerular injury, in which neutrophil transmigration across the endothelium is not required, effective functional inhibition of beta 2 integrin CAM in vivo did not reduce glomerular injury or glomerular neutrophil influx. These studies demonstrate that beta 2 integrin CAM are not a requirement for neutrophil accumulation and glomerular injury in anti-GBM GN in rabbits.
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PMID:Beta 2 integrin independent neutrophil recruitment and injury in anti-GBM glomerulonephritis in rabbits. 769 18

Intraglomerular expression of complement receptors (CR) was investigated chronologically in 22 repeatedly biopsied patients with membranoproliferative glomerulonephritis (MPGN) type I by indirect immunoperoxidase staining using MoAbs. Patients were divided into two groups based on whether intraglomerular C3c deposition was decreased at the second biopsy (2nd Bx) (group A, n = 12), or not (group B, n = 10). At the first biopsy (1st Bx), the severity of glomerular injury and the degree of glomerular C3c deposition were compatible between the two groups. Four patterns of CR1 (CD35) expression on podocytes were recognized: normal; generally decreased; focally/segmentally lost; and completely lost. The numbers of CR3 (CD11b/CD18)- and CR4 (CD11c/CD18)-positive cells per glomerular cross-section were counted. At the 1st Bx, no significant difference was found in the number of CR3+ or CR4+ cells between the two groups. At the 2nd Bx, the numbers of both the CR3+ and CR4+ cells were significantly decreased only in group A (P < 0.01). The numbers of CR3+ and CR4+ cells were significantly higher in cases with moderate or marked C3c deposits than in those with no or mild C3c deposits. The intensity of CR1 expression in group B was less than that in group A at both the 1st and 2nd Bx (1st, P < 0.05; 2nd, P < 0.01), and chronological improvement of CR1 expression was observed only in group A. The severity of glomerular injury was increased only in group B (P < 0.01), and was associated with persistent massive proteinuria and hypocomplementaemia. Our results suggest that, in cases with an adverse outcome, a more severe defect of CR1 initially exists and the expression of CR1 is not recoverable chronologically. This irreversible decrease or loss of CR1 may partly contribute to the continuous C3c deposition and intraglomerular infiltration of CR3+ and CR4+ cells.
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PMID:Participation of CR1 (CD35), CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in membranoproliferative glomerulonephritis type I. 774 66

No immunosuppression agent is as yet available that prevents the process of chronic allograft rejection, the most critical cause of late organ allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DNA synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the pathophysiology of the chronic phenomenon, we investigated the effects of the agent in an established model of chronic rejection of kidney allografts in a F344-to-Lewis rat strain combination. All recipients were treated for the first 10 days after engraftment with low-dose cyclosporine (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this model until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) was either initiated at the day of grafting (Gp 1) or 8 wks thereafter (Gp 2), and continued throughout the follow-up period. Non-RS61443-treated allografted rats receiving vehicle only (Gp 3) developed progressive proteinuria after 12 wk. Peak cellular infiltration (particularly macrophages in glomeruli and perivascular areas) at 16 wk was associated with densely expressed adhesion molecules (ICAM-1 on endothelium), cytokines and growth factors (TNF-alpha and TGF-beta in glomeruli and PDGF on arterial smooth muscle cells). Interstitial fibrosis, with tubular atrophy, glomerulosclerosis, and varying degrees of intimal proliferation and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allografted kidneys generally confirmed the immunohistological observations, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM-1). Serum-allospecific IgG and IgM peaked at 1-2 wk after engraftment in the control recipients, decreasing thereafter. Although IgM declined to baseline after 12 wk, low levels of allospecific IgG persisted throughout the follow-up period. In contrast, recipient treatment with RS61443 (both Gp 1 and Gp 2) allowed the allografts to function normally throughout follow-up period. Proteinuria was virtually absent, and morphological and immunohistological manifestations of the chronic process were markedly diminished. In addition, treated recipients developed no significant side effects, including leukopenia, anemia, thrombopenia, nephrotoxicity, and hepatotoxicity. It appears that this agent can safely prevent the changes of chronic rejection of kidney allografts in this rat model.
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PMID:Effects of RS61443 on functional and morphological changes in chronically rejecting rat kidney allografts. 787 46

The contribution of IL-1 to leukocyte infiltration in anti-glomerular basement membrane (GBM) antibody (Ab) glomerulonephritis (GN) was examined by the administration of a specific IL-1 receptor antagonist (IL-1ra). Lewis rats received anti-GBM Ab or normal rabbit serum and were treated with either 0.9% saline or 6 mg IL-1ra over a 24-h time period. Plasma IL-1ra concentration was 2,659 +/- 51 ng/ml 4 h after anti-GBM Ab and IL-1ra administration. PMN and monocyte/macrophage infiltration declined 39% (9.8 +/- 1.9 to 6.0 +/- 1.5 PMN/glomerulus, P < 0.001) and 29% (4.9 +/- 0.8 to 3.5 +/- 0.8 ED-1 cells/glomerulus, P = 0.002) with IL-1ra treatment at 4 h, respectively. Similarly, the number of glomerular cells staining for lymphocyte function-associated molecule-1 beta (CD18) declined 39% from 16.7 +/- 1.9 to 10.7 +/- 1.6 cells/glomerulus at 4 h (P = 0.0001). This was associated with a decrease in glomerular intracellular adhesion molecule-1 expression. The mean glomerular intracellular adhesion molecule-1 score in anti-GBM Ab GN rats treated with IL-1ra was less than that of rats administered anti-GBM Ab and 0.9% saline at 4 (2.0 +/- 0.2 vs 2.5 +/- 0.2, P < 0.05) and 24 (2.5 +/- 0.1 vs 3.1 +/- 0.2, P = 0.0001) h. These immunopathologic changes correlated with a 50% reduction in proteinuria from 147 +/- 34 to 75 +/- 25 mg/d (P < 0.002). Treatment with IL-1ra did not affect the steady state mRNA expression of either IL-1 beta or TNF alpha. An increase in the IL-1ra dose to 30 mg given within the initial 4 h provided no additional benefit. The decline in PMN and monocyte/macrophage infiltration of the glomerulus at 4 h was similar to that found in the initial study. Furthermore, the protective benefit of IL-1ra was abrogated by doubling the dose of the anti-GBM Ab GN, despite administering high dose IL-1ra (30 mg). In these studies, detectable IL-1ra was found in the serum of untreated anti-GBM Ab GN controls. These data suggest a positive yet limited role for IL-1ra in the therapeutic intervention of anti-GBM Ab GN.
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PMID:Interleukin-1 receptor antagonist ameliorates experimental anti-glomerular basement membrane antibody-associated glomerulonephritis. 790 69

Nephrotoxic nephritis (NTN), a model of autoimmune glomerulonephritis, is characterized by glomerular inflammation, which results in both proteinuria and an increase in eicosanoid production. In light of the ability of CD18 integrins to participate in leukocyte adherence (and thereby migration), we examined the role of the integrin CD11b/CD18 in NTN using OX42, a monoclonal antibody directed against rat CD11b. Administration of OX42 30 min before induction of NTN decreased proteinuria (by 50%) but did not affect the number of leukocytes found in the glomerulus or the accompanying increase in glomerular eicosanoid production. Administration of OX42 16 h before disease induction led to a more substantial decrease in proteinuria (80%) and, in contrast to 30 min pretreatment, decreased the number of neutrophils found in the glomerulus and the accompanying increase in glomerular eicosanoid production (both by 50%). OX42 pretreatment had no effect on the number of macrophages found in glomeruli. Circulating leukocytes from animals treated with OX42 in vivo showed saturating surface levels of antibody by fluorescence-activated cell sorting (FACS) analysis and normal upregulation of CD11b by pharmacological activation. Sixteen hours after in vivo injection of OX42, 50% more peripheral leukocytes were labeled relative to control leukocytes labeled with OX42 ex vivo. Glomerular leukocytes in NTN exhibited upregulated expression of CD11b relative to peripheral leukocytes. These data show that CD11b/CD18 may participate in the acute expression of glomerular damage in NTN in a fashion not wholly dependent on blocking neutrophil migration into glomeruli. Blockade of surface receptors (as opposed to inhibition of upregulation) is sufficient to obtain this effect.
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PMID:Attenuation of immune-mediated glomerulonephritis with an anti-CD11b monoclonal antibody. 809 79

We studied the expression of adhesion molecules on infiltrating leukocytes and tubular cells in chronic tubulointerstitial nephritis associated with puromycin aminonucleoside (PA) nephrosis. Rats received injections of PA (2 mg/100 g body wt) weekly for the first 3 weeks and every other week thereafter. Rats were killed at 0, 3, 5, 8, and 12 weeks after the start of injections. From the third to the fifth week, the initial infiltrating cells in interstitial tissue were mainly CD4+ T lymphocytes. At the fifth week, ICAM-1, CD44, and hyaluronate were expressed on infiltrating cells in interstitial tissue. At the eighth week, the number of infiltrating cells reached a peak and consisted of T lymphocytes (CD4, CD8) and macrophages (ED1, MHC class II, CD11b, and CD18). The severity of interstitial infiltration was correlated with the degree of proteinuria and with ICAM-1 expression. Our results suggest that CD4+ T lymphocytes may contribute to the production of initial tubular injury. Expression of ICAM-1 helps mononuclear cells migrate to the interstitium. In addition, expression of CD44 and hyaluronate may play important roles in the chronicity of tubulointerstitial nephritis.
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PMID:The relationship of adhesion molecules and leukocyte infiltration in chronic tubulointerstitial nephritis induced by puromycin aminonucleoside in Wistar rats. 863 80

Intercellular adhesion molecule-1 (ICAM-1, CD54), an adhesion molecule of the immunoglobulin superfamily, is an endothelial cell surface ligand for such leukocyte integrins as lymphocyte-function-associated molecule 1 (LFA-1, CD11a/CD18), Mac-1 (CD11b/CD18) and CD43. These molecules mediate adhesive interactions between leukocytes and endothelial cells and are critically involved in infiltration of leukocytes into inflammatory lesions. We examined the expression of ICAM-1 in renal tissues of Masugi nephritis rats and directly examined the role of ICAM-1 by administration of neutralizing monoclonal antibodies (MAbs) to rat ICAM-1, LFA-1 alpha-subunit (LFA-1 alpha), beta-subunit (LFA-1 beta) and Mac-1 alpha-subunit (Mac-1 alpha). Within 3 h after injection of nephrotoxic serum, increased expression of ICAM-1 was detected in the glomeruli by in situ hybridization and an immunofluorescence study. Proteinuria was significantly suppressed by the MAbs against ICAM-1, Mac-1 alpha and LFA-1 beta. Neutrophil infiltration into the glomeruli was significantly prevented by injection of the MAbs against ICAM-1, LFA-1 alpha and LFA-1 beta. These results indicate that both ICAM-1/LFA-1 and ICAM-1/Mac-1 pathways are involved in neutrophil infiltration into the glomeruli. On the other hand, monocytic infiltration was prevented by the MAbs against ICAM-1, LFA-1 alpha and LFA-1 beta but not by anti-Mac-1 alpha MAb. Due to these results, ICAM-1 is considered to be a critical molecule involved in the pathogenesis of the leukocyte infiltration into the glomeruli in the heterologous phase of Masugi nephritis. Anti-ICAM-1 antibody may be beneficial in the treatment of leukocyte-mediated glomerular diseases.
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PMID:The critical role of intercellular adhesion molecule-1 in Masugi nephritis in rats. 877 54

The mechanisms underlying leukocyte migration into inflamed glomeruli and their in situ activation are incompletely understood. We addressed this issue by investigating the effects of monoclonal antibodies (mAbs) to CD18 and VLA-4 on these process in the heterologous phase of anti-glomerular basement membrane (GBM) nephritis in rat. Anti-CD18 mAb substantially attenuated neutrophil (PMN) migration into glomeruli and the accompanying proteinuria which is a function of in situ leukocyte activation (ca. 60%). Anti-VLA-4 mAb modestly inhibited PMN migration (ca. 20%) and had no significant effect on proteinuria. Combination of both mAbs was no more effective than anti-CD18 mAb alone. Despite continued mAb blockade of CD18 or VLA-4 (or both), macrophage (M phi) migration following PMN influx was unaltered. However, combined CD18/VLA-4 mAbs diminished the proteinuria associated with M phi influx (ca. 50%). Abrogation of the acute influx of PMNs in this model (via complement depletion or anti-PMN antibody) did not diminish the following influx of M phi s, although the associated proteinuria was abolished. In this context, M phi migration was substantially decreased by anti-VLA-4 mAb (ca. 50%), but not anti-CD18 mAb (either alone or with anti-VLA-4 mAb). In sum, leukocyte migration and activation in the heterologous phase of anti-GBM nephritis are dependent on CD18 and VLA-4, although to varying degrees depending on the leukocyte subtype and the presence of prior inflammation. Nonetheless, a significant component of both PMN and M phi migration/activation is CD18/VLA-4 independent.
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PMID:Differing roles of CD18 and VLA-4 in leukocyte migration/activation during anti-GBM nephritis. 884 Feb 74

Peripheral blood leukocytes infiltrate the kidney in chronic serum sickness (CSS). We therefore studied the expression of CD54 and its ligands CD18 and CD11b/c in CSS in 10 rats with CSS, 6 rats immunized similarly who did not developed proteinuria (no-CSS group), and 10 normal rats (control group). Intense (6 to 35 times more than controls) leukocyte infiltration was observed in CSS. The CSS group over-expressed CD54 in glomeruli and interstitium in association with increments in CD18- and CD11b/c-positive cells ranging 2.5 to 7 times the number found in controls. 75% of infiltrating leukocytes expressed CD18 and 87% expressed CD11b/c. The non-CSS group had leukocyte infiltration and expression of adhesion molecules similar to control group. Adherence of CD43-positive cells to renal tissues was 4 times higher in renal tissue from CSS rats than to normal kidney. Pretreatment with corresponding Mabs reduced adherence by half. We concluded that over-expression of CD54 and its ligands CD18 and CD11b/c in infiltrating leukocytes occur in CSS. Binding experiments suggest the functional relevance of these molecules.
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PMID:Expression of adhesion molecules in chronic serum sickness in rats. 1008 Aug 31

Histological analyses have identified lymphocytes and macrophages as the predominant leukocyte populations that infiltrate organs undergoing chronic rejection. In order to define the time frame of this infiltration, we investigated the in vivo migration pattern of lymphocytes in a well-established rat model of chronic kidney allograft rejection. F344 kidneys were orthotopically transplanted into bilaterally nephrectomized Lewis rats. Recipients were treated with cyclosporin A (1.5 mg/kg/per day) for the first 10 days. After anti-CD18 or vehicle pretreatment, peripheral blood lymphocytes obtained from naive Lewis rats and labeled with 3H-uridine were injected into transplanted rats 12 and 16 weeks after transplantation. Organs were harvested 4, 8, and 12 h thereafter. After 12 weeks, proteinuria developed, accompanied by all signs of chronic rejection including glomerular sclerosis. Labeled lymphocytes rapidly infiltrated grafted kidneys 4 h after injection. Even more lymphocytes had accumulated in the grafts 12 h after injection. After 16 weeks, few lymphocytes had emigrated into the graft at 4 h, while infiltration was most pronounced by 12 h. Pretreatment with anti-CD18 inhibited the influx of lymphocytes. There was no difference between the patterns of lymphocytes derived from naive and transplanted rats. Our results emphasize the importance of endothelial cells in chronically rejecting kidneys for the control of leukocyte influx. Beta2-integrins may play a central role in determining the transendothelial migration during this process.
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PMID:In vivo migration of lymphocytes in chronically rejecting rat kidney allografts. 1036 98


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