Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the importance of T-lymphocytes in wound healing, we examined the effect of T-lymphocyte depletion on the healing of surgical wounds. Thirty Balb/c mice were injected intraperitoneally with 1 mg of rat anti-mouse (IgG2b) cytotoxic monoclonal antibody (30H12) against the Thy1.2 (all T) determinant. Twenty-four hours later animals showed a greater than 95% depletion of Thy1.2 cells in peripheral blood and spleen. Thirty control mice received nonspecific rat immunoglobulin (1 mg). Twenty-four hours after treatment mice underwent a 2.5 cm dorsal skin incision with subcutaneous placement of polyvinyl alcohol sponges. Injections were repeated at weekly intervals. Wound healing was assessed at 2, 3, and 4 weeks by the breaking strength of wound strips and by the hydroxyproline content of sponge granulomas (an index of wound reparative collagen deposition). Thy1.2 depletion at death was 95% to 57% in peripheral blood and 86% to 68% in the spleen. Both groups gained weight equally. We found that T cell depletion significantly impairs wound breaking strength and wound collagen deposition at all times studied. The data strongly suggest that T-lymphocytes modulate fibroblast activity during normal wound healing.
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PMID:Significance of T-lymphocytes in wound healing. 349 61

Osteogenic cells were sorted from bone marrow of 5-fluorouracil (5-FU)-treated mice based on light scatter characteristics, Sca-1 expression, and their binding to wheat germ agglutinin (WGA). Four sort gates were established using forward (FSC) and perpendicular (SSC) light scatter and were denominated as FSChigh SSClow, FSClow SSChigh, FSClow SSClow, and FSChigh SSChigh cell. Cells from the FSChigh SSChigh gate, but not from the other gates, synthesized alkaline phosphatase, collagen, and osteocalcin and formed a mineralized matrix in culture. The number of osteoprogenitor cells was significantly enriched after depleting the 5-FU bone marrow from cells of the lymphoid and myeloid lineage, eg, T cells, B cells, natural killer cells, granulocytes, macrophages, and erythrocytes. Approximately 95% of the FSChigh SSChigh cell population of this "lineage-negative" (Lin-) marrow expressed the Sca-1 antigen (Sca-1+) and bound WGA. Three additional sort windows were established based on WGA binding intensity and were denominated as Sca-1+ WGAdull, Sca-1+ WGAmedium, and Sca-1+ WGAbright. Cells from the Sca-1+ WGAbright gate, but not from the other gates, synthesized bone proteins and formed a mineralized matrix. However, they lost this capacity upon subcultivation. Further immunophenotypic characterization showed that FSChigh SSChigh Lin- Sca-1+ WGAbright cells expressed stromal (KM16) and endothelial (Sab-1 and Sab-2) markers, but not hematopoietic surface markers such as c-kit and Thy1.2. Sorted FSChigh SSChigh Lin- Sca-1+ WGAbright cells form three-dimensional nodules that stain with the von Kossa technique and contain osteoblast and osteocyte-like cells.
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PMID:Characterization and purification of osteogenic cells from murine bone marrow by two-color cell sorting using anti-Sca-1 monoclonal antibody and wheat germ agglutinin. 751 72

Glomerular injury is characterized by mesangial cell (MC) proliferation and matrix formation. We sought to determine if reducing the activity of cyclin-dependent kinase 2 (CDK2) with the purine analogue, Roscovitine, decreased MC proliferation in vitro and in vivo. Roscovitine (25 microM) inhibited FCS-induced proliferation (P < 0.0001) in cultured MC. Rats with experimental mesangial proliferative glomerulonephritis (Thy1 model) were divided into two groups. A prevention group received daily intraperitoneal injections of Roscovitine in DMSO (2.8 mg/kg) starting at day 1. A treatment group received daily Roscovitine starting at day 3, when MC proliferation was established. Control Thy1 rats received DMSO alone. MC proliferation (PCNA +/OX7 + double immunostaining) was reduced by > 50% at days 5 and 10 in the Roscovitine prevention group, and at day 5 in the treatment group (P < 0.0001). Early administration of Roscovitine reduced immunostaining for collagen type IV, laminin, and fibronectin at days 5 and 10 (r = 0.984; P < 0.001), which was associated with improved renal function (urinary protein/creatinine, blood urea nitrogen, P < 0.05). We conclude that reducing the activity of CDK2 with Roscovitine in experimental glomerulonephritis decreases cell proliferation and matrix production, resulting in improved renal function, and may be a useful therapeutic intervention in disease characterized by proliferation.
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PMID:Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist. 936 65

Inhibition of 3-hydro-3-methylglutaryl coenzyme A reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types. Therefore, 3-hydro-3-methylglutaryl coenzyme A reductase inhibitors may have a beneficial effect in glomerular disease, because glomerular cell proliferation is a central feature in the active glomerular injury. This study examines the effect of simvastatin on glomerular pathology in a rat mesangial proliferative glomerulonephritis (GN) induced by anti-thymocyte antibody (anti-Thy 1.1 GN). There was no difference in the degree of the antibody and complement-mediated initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation. The proliferative activity was maximal at day 4 after disease induction (26.5+/-7.0 of proliferating cell nuclear antigen-positive cells/glomerulus); however, approximately 70% of proliferation was suppressed by simvastatin treatment. At day 4 after disease induction, simvastatin administration also decreased alpha-smooth muscle actin expression in the glomerulus, which is a marker for mesangial cell activation. Inhibition of monocyte/macrophage recruitment into glomeruli by simvastatin was also a prominent feature. There was a 30% decrease in the number of glomerular ED-1+ cells by simvastatin treatment at day 2 after disease induction. Furthermore, simvastatin remarkably suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. We also found that the platelet-derived growth factor expression was reduced in simvastatin-treated nephritic rats, which might simply reflect the reduction in mesangial cell proliferation and mesangial cellularity. There was no significant difference in plasma cholesterol or triglyceride levels between simvastatin- and vehicle-treated nephritic rats at day 2 and day 4, which corresponded to the times when simvastatin treatment resulted in a reduction in mesangial cell proliferation. In conclusion, this is the first report to find that mesangial cell proliferation and matrix expansion have been blocked by simvastatin in vivo. The protective effect of simvastatin in the matrix expansion in anti-Thy1.1 GN was partly by inhibition of mesangial cell proliferation and monocyte/ macrophage recruitment into glomeruli, which were independent of a change in circulating lipids.
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PMID:Simvastatin suppresses glomerular cell proliferation and macrophage infiltration in rats with mesangial proliferative nephritis. 980 88

Galectin-3 is a beta-galactoside-binding protein synthesized by macrophages and other inflammatory cells and expressed in various branching epithelia, including the developing kidney. The expression of galectin-3 has been studied in a rat model of acute mesangial proliferative glomerulonephritis in which a single injection of anti-Thy1.1 antibodies leads to destruction of mesangial cells expressing a Thy1.1 epitope on their surface. The glomerular lesion is characterized by expansion of the mesangial matrix, especially laminin and collagen type IV, and mesangial hypercellularity. Galectin-3 expression, which is sparse in mature rat kidney and confined to the apical face of some distal tubules, is increased within 1-3 days following antibody administration, with the recruitment of glomerular macrophages and pronounced neo-expression in the cytoplasm and at the basal face of distal tubules. At later times, galectin-3 is detected immunohistochemically in the repopulating mesangial cell mass, preceding the extensive mesangial deposition of laminin and collagen type IV. Mesangial cells in culture do not produce appreciable amounts of galectin-3 but do bind and endocytose exogenously added lectin. Addition of galectin-3 to primary cultures of mesangial cells prepared from normal rats induces a 1.5-fold increase in the synthesis of collagen type IV and it also acts in synergy with a quantitatively similar stimulatory effect of transforming growth factor beta (TGF-beta) on matrix synthesis. Exogenous galectin-3 prolongs the survival of mesangial cells in serum-free cultures and also protects these cells against cytotoxic effects of TGF-beta. The data support the notion that the increased expression and secretion of galectin-3 in infiltrating macrophages and in distal tubular epithelia, together with up-regulation of IL-1beta and TGF-beta genes, play a role in mesangial hypercellularity in the progression of one model of inflammatory renal disease.
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PMID:Galectin-3 modulates rat mesangial cell proliferation and matrix synthesis during experimental glomerulonephritis induced by anti-Thy1.1 antibodies. 1039 10

Transforming growth factor-beta1 (TGF-beta 1) overexpression plays a key role in the glomerular accumulation of extracellular matrix proteins in renal disease. Retinoids have previously been shown to significantly limit glomerular damage in rat experimental glomerulonephritis. Therefore, the effects of all-trans retinoic acid and isotretinoin on the components of the TGF-beta system and extracellular matrix proteins in anti-Thy1.1-nephritis (Thy-GN) were investigated. Vehicle-injected control rats were compared with rats treated with daily subcutaneous injections of 10 mg/kg body wt all-trans retinoic acid or 40 mg/kg body wt isotretinoin (n = 9 per group) either with a pretreatment (day -2 through 8) or posttreatment protocol (day +3 through 8), i.e., starting before or after induction of Thy-GN, respectively. Urinary TGF-beta 1 excretion was 60% lower in all-trans retinoic acid-treated animals with Thy-GN (P < 0.025). The increase of cortical TGF-beta 1 gene expression in Thy-GN rats was significantly attenuated with all-trans retinoic acid and even more with isotretinoin treatment as compared with untreated animals (P < 0.025). Cortical expression of TGF receptor II, but not receptor I gene expression, was significantly lower in animals treated with all-trans retinoic acid or isotretinoin (P < 0.05). In all-trans retinoic acid-treated animals with Thy-GN, the increase of glomerular TGF-beta 1 protein (P < 0.008) and TGF-beta 1 (P < 0.025) and TGF receptor II mRNA (P < 0.015) was significantly less. Immunohistochemistry revealed less glomerular staining for TGF-beta 1 and TGF receptor II in the presence of all-trans retinoic acid. TGF-beta 1 immunostaining was not restricted to monocytes and macrophages, as indicated by double-staining. Glomerular staining for collagen IV and collagen III was less in animals treated with isotretinoin (P < 0.02 for both) in contrast to all-trans retinoic acid, whereas fibronectin remained unchanged. It was concluded that the beneficial effects of retinoids on glomerular damage are presumably due to a marked reduction in renal TGF-beta 1 and TGF receptor II expression.
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PMID:Effects of retinoids on the TGF-beta system and extracellular matrix in experimental glomerulonephritis. 1167 6

Hematopoietic and hepatic stem cells share characteristic markers such as CD34, c-kit, and Thy1. Based on the recent observations that hepatocytes may originate from bone marrow, we investigated the potential of CD34(+) bone marrow cells to differentiate into hepatocytic cells in vitro. CD34(+) and CD34(-) human bone marrow cells were separated by magnetic cell sorting. Cells were cultured on a collagen matrix in a defined medium containing hepatocyte growth factor. Cell count and size were measured by flow cytometry, and reverse transcription polymerase chain reaction was carried out for the liver-specific markers CK-19 and albumin. During cell culture, CD34(+) cells showed an increasing cell number and proliferative activity as assessed by Ki-67 staining. Under the specified culture conditions, CD34(+) cells expressed albumin RNA and CK-19 RNA after 28 days, whereas CD34(-) cells did not show liver-specific gene expression. The results indicate that CD34(+) adult human bone marrow stem cells can differentiate into hepatocytic cells in vitro.
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PMID:Liver-specific gene expression in cultured human hematopoietic stem cells. 1252 56

Focal segmental glomerulosclerosis (FSGS) is a hallmark of progressive renal disease. Podocyte injury and loss have been proposed as the critical events that lead to FSGS. In the present study, the authors have examined the development of FSGS in Thy-1.1 transgenic (tg) mice, with emphasis on the podocyte and parietal epithelial cell (PEC). Thy-1.1 tg mice express the Thy-1.1 antigen on podocytes. Injection of anti-Thy-1.1 mAb induces an acute albuminuria and development of FSGS lesions that resemble human collapsing FSGS. The authors studied FSGS lesions at days 1, 3, 6, 7, 10, 14, and 21, in relation to changes in the expression of specific markers for normal podocytes (WT-1, synaptopodin, ASD33, and the Thy-1.1 antigen), for mouse PEC (CD10), for activated podocytes (desmin), for macrophages (CD68), and for proliferation (Ki-67). The composition of the extracellular matrix (ECM) that forms tuft adhesions or scars was studied using mAb against collagen IV alpha2 and alpha4 chains and antibodies directed against different heparan sulfate species. The first change observed was severe PEC injury at day 1, which increased in time, and resulted in denuded segments of Bowman's capsule at days 6 and 7. Podocytes showed foot process effacement and microvillous transformation. There was no evidence of podocyte loss or denudation of the GBM. Podocytes became hypertrophic at day 3, with decreased expression of ASD33 and synaptopodin and normal expression of WT-1 and Thy-1.1. Podocyte bridges were formed by attachment of hypertrophic podocytes to PEC and podocyte apposition against denuded segments of Bowman's capsule. At day 6, there was a marked proliferation of epithelial cells in Bowman's space. These proliferating cells were negative for desmin and all podocyte markers, but stained for CD10, and thus appeared to be PEC. The staining properties of the early adhesions were identical to that of Bowman's capsule, suggesting that the ECM in the adhesions was produced by PEC. In conclusion, the authors propose the following sequence of events leading to FSGS lesions in the Thy1.1 tg mice: (1) PEC damage and denudation of Bowman's capsule segments; (2) podocyte hypertrophy and bridging; and (3) PEC proliferation with ECM production.
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PMID:The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice. 1503 95

Fibronectin (FN) is the main extracellular matrix component in glomerulosclerotic lesions. There are different FN isoforms that result from alternative splicing at the EDA and EDB regions of FN mRNA. Increased inclusion of EDA and EDB, which can be elicited by TGFbeta, may be conducive to the development of glomerulosclerosis (GS). TGFbeta and IL-4 have previously been shown to play a role in the development of GS. In this study, the mRNA splicing patterns for EDA+ and EDB+ fibronectin were investigated in vivo in various experimental sclerotic glomerulopathies, in vitro in rat mesangial cells (MC) that were stimulated by TGFbeta or transfected with IL-4, and in human kidney biopsies with GS from patients with various kidney diseases. Analysis of glomerular FN mRNA demonstrated inclusion of both ED regions in rats with anti-Thy1 nephritis or chronic serum sickness and in mice with anti-GBM glomerulonephritis. Inclusion of both the EDA and EDB regions was associated with glomerular TGFbeta expression. In contrast, in mice with Th2-mediated graft-versus-host disease, a model for lupus nephritis, the FN transcripts included neither the EDA nor the EDB region, and renal TGFbeta expression was absent. Compared to normal MCs in culture, MCs transfected with IL-4 produced lower amounts of FN and demonstrated less EDA inclusion, while MC that had been treated with TGFbeta showed increased production of FN and more EDA inclusion. Renal biopsies from patients with renal diseases, except those taken from patients with lupus nephritis, showed higher TGFbeta levels, higher FN levels, and more EDA inclusion than controls. TGFbeta may be a key player in the development of GS by inducing local FN production and alternative splicing of FN mRNA. In lupus glomerulonephritis, in which the involvement of TGFbeta in GS is less prominent, Th2 cytokines such as IL-4 probably account for increased intrarenal collagen synthesis and subsequent FN accumulation from the circulation. In conclusion, neither alternative FN splicing, nor a high transcription level of TGFbeta, appears to be a general prerequisite for the development of GS.
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PMID:Alternatively spliced isoforms of fibronectin in immune-mediated glomerulosclerosis: the role of TGFbeta and IL-4. 1537 54

Mesangial cell proliferation is a significant event in the development of progressive glomerular injuries. However, the issue of how cell proliferation is involved in the development of glomerulosclerosis is unclear. Recently, we showed that the overexpression of type IV collagen (Col IV), a major component of mesangial extracellular matrix, is transcriptionally regulated by Smad1 in diabetic glomerulosclerosis. In this study, we have demonstrated the effect of the administration of an anti-platelet-derived growth factor (PDGF) beta-receptor antibody (APB5) blocking activation by the PDGF-B chain on rat glomerulonephritis and have examined the signaling pathways that regulate both glomerular cell proliferation and glomerulosclerosis in vivo and in vitro. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, mesangial cell proliferation and the expression of Col IV peaked at day 6. Immunohistochemical staining for the expression of Smad1, phospho-Smad1 (pSmad1), and phospho-STAT3 (pSTAT3) revealed that the peak for glomerular Smad1 expression occurred at day 6, consistent with the peak for mesangial proliferation. The expression of pSmad1 was up-regulated at day 1, and the peak for glomerular pSmad1 expression occurred at day 4 of the disease. When treated with APB5, both mesangial proliferation and sclerosis were reduced significantly. The expression of Smad1, pSmad1, and pSTAT3 was also significantly reduced by the administration of APB5. PDGF induced both mesangial cell replication and Col IV synthesis in association with an increased expression of pSTAT3 and pSmad1 on cultured mesangial cells. In addition, APB5 reduced mesangial cell proliferation in association with decreased pSmad1, pSTAT3, and Col IV protein expressions in vitro. The introduction of dominant negative STAT3 significantly decreased the expression of Col IV in cultured mesangial cells. These data suggest that the activation of STAT3 and Smad1 participates in the developing process of glomerulosclerosis in experimental glomerulonephritis.
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PMID:Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis. 1559 Oct 53


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