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 P-selectin in T-lymphocyte accumulation and injury was studied in delayed-type hypersensitivity (DTH) responses in the skin and glomeruli of rats. Sprague Dawley rats were sensitized to sheep globulin and challenged 5 days later in the skin by subcutaneous injection and simultaneously in glomeruli by intravenous injection of a subnephritogenic dose of sheep anti-rat glomerular basement membrane globulin. This resulted in cutaneous and glomerular T lymphocyte-dependent macrophage influx and injury characteristic of DTH. Up-regulation of P-selectin expression on endothelial cells was observed in both inflammatory lesions. Treatment of rats with anti-CD5 antibody immediately prior to antigen challenge prevented the development of injury as assessed by measurement of proteinuria and skin swelling, as well as local T cell and macrophage accumulation in the glomerulus and in the skin, but did not block up-regulation endothelial cell P-selectin. Treatment with anti-CD4 antibody produced similar results. Blocking P-selectin in vivo with a functionally inhibitory antibody prevented development of proteinuria and skin swelling following antigen challenge. Local accumulation of T cells and macrophages was markedly attenuated in glomeruli and the skin and up-regulation of endothelial cell P-selectin was prevented. These data demonstrate that P-selectin is locally up-regulated on endothelial cells in T cell-dependent glomerular and cutaneous inflammation and suggests a pivotal functional role for P-selectin in local T cell recruitment and subsequent injury in DTH.
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PMID:P-selectin directs T lymphocyte-mediated injury in delayed-type hypersensitivity responses: studies in glomerulonephritis and cutaneous delayed-type hypersensitivity. 861 18

P-selectin present on surfaces of activated endothelium and platelets mediates neutrophil-endothelial and neutrophilplatelet interactions. The role of P-selectin in vivo was examined in a model of acute passive anti-GBM nephritis in P-selectin-deficient and wild-type mice which was induced by intravenous injection of anti-GBM serum. There were two major differences between P-selectin-deficient and wild-type mice. Firstly, mutant mice had approximately two fold more glomerular PMNs and albuminuria than wild-type animals at the peak of neutrophil influx and proteinuria. Secondly, Lipoxin A4 (LXA4), an eicosanoid which inhibits leukocyte-endothelial adhesion in vitro, and is generated primarily by transcellular biosynthetic routes during P-selectin-mediated platelet-PMN interaction [1], was approximately 60% of wild type levels in nephritic kidneys of P-selectin-deficient mice. Injection of wild-type platelets into P-selectin-null mice restored LXA4 to wild-type levels. The corresponding PMN influx approximated PMN levels in wild-type mice receiving platelets but urine albuminuria remained higher. Although these two P-selectin-dependent events cannot be directly linked, our results point to the importance of considering both platelet and endothelial P-selectin in determining the cellular events in inflammation.
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PMID:Acute passive anti-glomerular basement membrane nephritis in P-selectin-deficient mice. 873 Oct 99

P-selectin is one of the key early mediators of leukocyte adhesion in inflammatory conditions. This report examines the role of P-selectin in a neutrophil- and platelet-mediated model of glomerulonephritis (the concanavalin A [con A] model). The administration of neutralizing anti-P-selectin antibody (PB 1.3) reduced the platelet influx at 10 min (P < 0.05) and was associated with a 60% reduction in the neutrophil infiltrate and a 50% reduction in the number of oxidant-producing cells at 3 h within glomeruli. No effect on glomerular monocyte-macrophage accumulation was observed, and proteinuria was reduced by 20% but did not reach significance. It is concluded that P-selectin plays an important role in mediating the neutrophil and platelet accumulation in this model and likely has a role in mediating the glomerular injury.
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PMID:A role for P-selectin in neutrophil and platelet infiltration in immune complex glomerulonephritis. 940 85

This experiment was performed to study the roles of intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen-1 (LFA-1), and another adhesion molecule, selectin, in the development of cationized antigen-induced in situ immune complex glomerulonephritis (CAICGN). CAICGN was induced in preimmunized rats by perfusing cationized human immunoglobulin G (CaIgG) through the left kidney. Albuminuria developed within 2 days of CaIgG perfusion and peaked around day 7. Marked polymorphonuclear leukocyte (PMN) infiltration was observed in the glomeruli 1 hour after CaIgG perfusion, but the infiltrate resolved by day 7. Immunofluorescent studies disclosed linear deposition of rat IgG and C3 along glomerular capillary walls 1 hour after CaIgG perfusion. Treatment with monoclonal antibodies (mAbs) to both ICAM-1 and LFA-1, as well as with a sulfatide, a ligand of L- and P-selectin, started within 2 days after CaIgG perfusion completely suppressed the development of proteinuria without affecting the glomerular deposition of immunoreactants. Although sulfatide attenuated the PMN response 1 hour after CaIgG perfusion, ICAM-1 and LFA-1 mAb treatment did not alter PMN infiltration. Treatment with ICAM-1 and LFA-1 mAbs started on day 5, or treatment with sulfatide started on day 4, after CaIgG perfusion did not affect albuminuria. These findings suggest that adhesion molecules play an important role in the development of proteinuria in CAICGN. The contribution of these molecules was evident for only a short interval after the induction of nephritis, when a significant infiltration of PMNs was observed.
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PMID:Cell-to-cell interaction is required to induce proteinuria in in situ immune complex glomerulonephritis. 970 72

P-selectin is a leukocyte adhesion receptor present in endothelial cells and platelets. We examined the role of P-selectin in the autologous phase of an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis using P-selectin-deficient mice and chimeric mice expressing P-selectin only in platelets or endothelial cells. P-selectin-deficient mice exhibited more severe glomerular damage with increased interstitial mononuclear leukocytic infiltrates, and had significantly increased proteinuria and mortality when compared to wild-type mice. P-selectin on the endothelium was predominantly responsible for protection from the exacerbated disease, because chimeric mice with endothelial P-selectin, and not mice with platelet P-selectin, showed glomerular injury similar to that in wild-type animals. Levels of soluble circulating P-selectin were increased in nephritic wild-type mice and in chimeric mice with endothelial P-selectin, but not platelet P-selectin. Levels of soluble P-selectin, which has been shown to be anti-inflammatory in vitro, were inversely associated with the severity of disease. P-selectin was not expressed in the endothelium of the glomerulus or interstitium. Thus, the protective effect in wild-type mice may be accounted for, in part by soluble P-selectin shed by non-renal endothelial cells, although other endothelial P-selectin-dependent mechanisms cannot be ruled out.
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PMID:P-selectin deficiency exacerbates experimental glomerulonephritis: a protective role for endothelial P-selectin in inflammation. 1007 81

Leukocytes play a central role in the pathogenesis of anti-glomerular basement membrane glomerulonephritis (anti-GBM GN). Understanding the mechanisms underlying their recruitment in the glomerulus is of critical importance, because this may lead to more specific anti-inflammatory drug design. The requirement for integrins, especially from the beta2 group, and their Ig superfamily counter-receptors has been established, however, the role of selectins remains controversial. An intravital microscopy technique was developed to study concomitantly the glomerular and venular leukocyte kinetics and the hemodynamic alterations in a rat model of anti-GBM GN, induced by injection of 10 mg of nephrotoxic serum (NTS). Histologic studies of the kidney were performed in parallel and urinary protein excretion was measured. The animals received NTS alone or were pretreated with either a monoclonal antibody against the beta2 integrin CD11b (OX42, 4 mg/kg) or fucoidan F7 (FF7, 8 mg/kg), an oligosaccharide that blocks both L- and P-selectin function. Administration of NTS resulted in a time-dependent increase in the number of adherent leukocytes in the glomeruli and a parallel decrease of the perfused glomerular capillary area. Substantial proteinuria was observed. Pretreatment with OX42 significantly attenuated these changes. FF7 almost abolished the rolling of the leukocytes in the venules, thus demonstrating efficient anti-selectin activity. Nevertheless, FF7 had no influence on the glomerular events or on the development of proteinuria. These results confirm that glomerular leukocyte adhesion in anti-GBM GN is CD11b-dependent. However, selectin-mediated interaction between the leukocytes and the glomerular capillary endothelium does not appear to be a prerequisite for leukocyte adhesion in the glomerulus. These results therefore question the potential utility of anti-selectin therapy in the treatment of anti-GBM GN.
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PMID:The role of selectins in glomerular leukocyte recruitment in rat anti-glomerular basement membrane glomerulonephritis. 1058 89

The influence of endogenous glucocorticoids (GC) on glomerular injury was studied in a rat model of heterologous anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Sprague-Dawley rats underwent adrenalectomy (ADX) or sham-operation 3 days prior to i.v. administration of both nephritogenic (100 microgram/g) and subnephritogenic (50 microgram/g) doses of sheep anti-rat GBM globulin. Administration of a subnephritogenic dose of anti-GBM globulin resulted in GN in adrenalectomized animals only. Similarly, ADX performed prior to administration of anti-GBM in the nephritogenic dose range resulted in exacerbation of GN compared with sham-operated animals (24 h protein excretion: 190.8 +/- 32.8 versus 42.5 +/- 2.6 mg/24 h; P < 0.005). In ADX animals receiving subnephritogenic doses of anti-GBM injury was manifested by abnormal proteinuria (62.7 +/- 5.8 mg/24 h), accumulation of neutrophils which peaked at 6 h (7.2 +/- 1.37 neutrophils per glomerular cross-section (neut/gcs)) and macrophage accumulation in glomeruli at 24 h (6.8 +/- 1.2 macrophages/gcs). Sham-adrenalectomized animals given the same dose of anti-GBM globulin developed minimal or no glomerular injury: urinary protein excretion (8.7 +/- 1.5 mg/24 h, P < 0.001); neutrophils (0.2 +/- 0.04 neutrophils/gcs, P < 0.001); macrophages (1.2 +/- 0.5 macrophages/gcs, P < 0.001). The increased cellular recruitment to glomeruli in adrenalectomized animals was associated with glomerular endothelial P-selectin expression. P-selectin expression was not detected in sham-operated rats after anti-GBM injection. Complement deposition in glomeruli was minimal in both groups. Physiologic GC replacement of ADX rats receiving subnephritogenic-dose anti-GBM reversed the observed susceptibility to GN development, with urinary protein excretion (7.8 +/- 1.12, P < 0.005) and no detectable P-selectin expression or leucocyte accumulation in glomeruli. These results suggest that endogenous GC modulate heterologous anti-GBM nephritis in rats and that this may be attributable, in part, to regulation of P-selectin expression.
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PMID:Endogenous glucocorticoids modulate experimental anti-glomerular basement membrane glomerulonephritis. 1060 78

The ability of interleukin-10 (IL-10) to inhibit macrophage recruitment, activation, and proliferation in vivo was studied in a macrophage-mediated, but T cell-independent, passive anti-glomerular basement membrane antibody-induced model of glomerulonephritis (GN) in rats. Treatment with recombinant murine IL-10 resulted in dose-dependent reductions in proteinuria (high dose: 16 +/- 1 mg/24 h; low dose: 30 +/- 2 mg/24 h; control treatment: 69 +/- 6 mg/24 h; normal: 7 +/- 1 mg/24 h) and glomerular macrophage recruitment (high dose: 1.8 +/- 0.1 macrophages per glomerular cross section [c/gcs]; low dose: 5.5 +/- 0.2 c/gcs; control treatment: 12.1 +/- 0.6 c/gcs). Macrophage and intrinsic glomerular cell proliferation were reduced at both doses of IL-10, as was glomerular expression of P-selectin and monocyte chemoattractant protein-1. IL-10 treatment also resulted in a dose-dependent reduction of macrophage activation as indicated by MHC class II and IL-1beta expression. Glomerular nitrite production by isolated cultured glomeruli was reduced after IL-10 treatment in vivo (high dose: 2.3 +/- 2.3 nmol/10(4) glomeruli per 72 h; low dose: 28 +/- 5 nmol/10(4) glomeruli per 72 h; control treatment: 82 +/- 11 nmol/10(4) glomeruli per 72 h). Tumor necrosis factor-alpha production was abolished by high-dose treatment and reduced by the lower dose (3.8 +/- 3.8 pg/10(4) glomeruli per 72 h; control treatment: 249 +/- 23 pg/10(4) glomeruli per 72 h). These studies demonstrate that IL-10 directly attenuates glomerular macrophage recruitment, activation, and proliferation in vivo and can significantly attenuate macrophage-mediated GN independent of any effects on T cells.
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PMID:Interleukin-10 inhibits macrophage-induced glomerular injury. 1066 33

Leucocytes infiltrate into renal tissue and are involved in the pathogenesis of crescentic glomerulonephritis. The initial event in the process of leucocyte infiltration is characterized by selectin-mediated leucocyte rolling on endothelial surface. Role of selectins in pathogenesis of glomerulonephritis has still been controversial. Sulphated glycolipids and sulphated polysaccharides interfere with the binding of P- and L-selectin with carbohydrate ligands on endothelial cells or on leucocytes. Here we evaluated the role of selectins and the preventive effects of sulphated colominic acid (SCA), a synthetic sulphated polysaccharide, on experimental crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats. Crescentic glomerulonephritis was induced by injection of nephrotoxic serum (NTS) in WKY rats. Rats subsequently received intraperitoneal injection of saline, neutralizing or non-neutralizing monoclonal antibody (mAb) to rat P-selectin and L-selectin, SCA (5 or 10mg/kg/day) or nonsulphated colominic acid (CA) (10mg/kg/day) for 2 weeks. Localization of P-, E-selectin, ligands for L-selectin and intraglomerular leucocytes was examined by immunohistochemistry. Gene expression of platelet-derived growth factor (PDGF) B chain in glomeruli was quantified using real-time RT-PCR. P-selectin was highly expressed on glomerular endothelial cells after injection of NTS, whereas E-selectin and L-selectin ligands were not detected. Anti-P-selectin mAb, but not anti-L-selectin mAb, significantly reduced glomerular infiltration of macrophages, crescent formation, and proteinuria. SCA also reduced proteinuria, macrophage infiltration, and crescent formation in a dose-dependent manner. Furthermore, SCA suppressed gene expression of PDGF B chain in glomeruli. Our results indicate that P-selectin partially mediates glomerular infiltration of macrophage in experimental crescentic glomerulonephritis. Moreover, SCA may inhibit intraglomerular infiltration of macrophages by interfering with P-selectin-dependent adhesion pathway, and progression of experimental crescentic glomerulonephritis.
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PMID:Preventive effect of sulphated colominic acid on P-selectin-dependent infiltration of macrophages in experimentally induced crescentic glomerulonephritis. 1210 15

The initial event in the process of leukocyte infiltration is characterized by leukocyte rolling on the surface of the endothelium, which is mediated by selectins. P- and L-selectin bind to the sulphated sugar chains of their natural ligands, including sulphated glycolipids such as sulphatide. Recently, it has been demonstrated that sulphated glycolipids and sulphated oligosaccharides interfere with selectin binding pathways. This study synthesized sulphated hyaluronic acid (SHA), which is a potential selectin-blocking agent, and examined its therapeutic effect on the experimental progressive mesangial proliferative glomerulonephritis induced by anti-Thy-1 monoclonal antibody (1-22-3 MAb) after unilateral nephrectomy. The selectin-inhibitory effect of SHA in vitro was confirmed. SHA inhibited the binding of P- and L-selectin to sulphatide, which is a glycolipid ligand for P- and L-selectin, at a concentration of 1.5 micro g/ml and 100 micro g/ml. Immunohistochemical examination showed that P-selectin was up-regulated in the glomeruli in the 1-22-3 MAb nephritis model, while the ligands for L-selectin were not detected in the glomerular tufts. A single administration of SHA ameliorated proteinuria and glomerular leukocyte infiltration in 24 h after the injection of anti-Thy-1 MAb. Anti-P-selectin MAb, but not anti-L-selectin MAb, inhibited proteinuria and glomerular leukocyte infiltration. To examine further the therapeutic effect of SHA on chronic glomerulonephritis, SHA was administered daily from day 3 to day 14 in this model. Proteinuria and glomerular leukocyte infiltration were significantly diminished in SHA-treated rats on day 14. These results suggest that SHA ameliorated rat progressive mesangial proliferative glomerulonephritis by inhibiting P-selectin-dependent leukocyte infiltration in glomeruli. Sulphated oligosaccharides may be beneficial for the therapy of mesangial proliferative glomerulonephritis.
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PMID:Therapeutic effect of sulphated hyaluronic acid, a potential selectin-blocking agent, on experimental progressive mesangial proliferative glomerulonephritis. 1237 74


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