Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is an important effector molecule of the inflammatory response. It is synthesized by mesangial cells and has been proposed to contribute to glomerular injury in various disease states. We studied whether NO modulates extracellular matrix production in cultured rat mesangial cells. Stimulation of rat mesangial cell NO release with gamma-interferon and lipopolysaccharide resulted in reduced production of collagen (by 35%) fibronectin (by 48%) (P < 0.05). In contrast, laminin synthesis was enhanced two-fold by the same maneuver (P < 0.05). These changes were reversed by the addition of L-NAME, a selective inhibitor of inducible nitric oxide synthase. This is the first demonstration that NO regulates the synthesis of extracellular matrix by mesangial cells. The results indicate that increased renal production of NO in glomerular diseases may attenuate the production and accumulation of matrix proteins and limit the severity of glomerulosclerosis.
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PMID:Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. 785 53

In addition to participating in protein synthesis in cells and tissues, L-arginine is essential for the synthesis of urea, creatine, creatinine, nitric oxide, and agmatine and influences hormonal release and the synthesis of pyrimidine bases. This places L-arginine, its precursors and its metabolites at the center of the interaction of different metabolic pathways and interorgan communication. Thus L-arginine participates in changing the internal environment in different but simultaneous ways, ranging from disposal of protein metabolic waste, muscle metabolism, vascular regulation, immune system function, and neurotransmission, to RNA synthesis and hormone-mediated regulation of the internal milieu. In normal rats, inhibition of the nitric oxide pathway results in systemic hypertension and decreased glomerular filtration rate and effective renal plasma flow. If the inhibition of this pathway is sustained, then glomerulosclerosis and death from uremia follow. Dietary intervention with L-arginine has resulted in amelioration of a number of experimental kidney diseases, such as those caused by subtotal nephrectomy, diabetic, nephropathy, cyclosporin A administration, salt-sensitive hypertension, ureteral obstruction, puromycin amino-nucleoside nephrosis, kidney hypertrophy due to high-protein feeding, and glomerular thrombosis due to administration of lipopolysaccharide. The present review addresses the current evidence for the beneficial effects of dietary intervention with L-arginine in a number of experimental renal diseases and describes the basis for the concept of L-arginine deficiency (absolute or relative) in certain settings in which supplementation of the diet with this amino acid may be beneficial.
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PMID:Role of arginine in health and in renal disease. 809 48

Patients with human immunodeficiency virus (HIV) infection are prone to the development of focal segmental glomerulosclerosis, a lesion in which increased mesangial cell proliferation and matrix synthesis may play a role. We undertook the present study to determine whether HIV sera may affect mesangial cell proliferation and matrix synthesis either directly or indirectly via effects on macrophage supernatants. Pooled HIV sera was found to significantly enhance (P < 0.01) mesangial cell proliferation in a concentration-related manner. Mesangial cell proliferation was significantly suppressed by two medications commonly utilized in HIV-infected patients, azidothymidine and trimethoprim/sulfamethoxazole, and was not significantly altered by lipopolysaccharide, suggesting that these medications as well as recurrent infection are unlikely to account for the proliferative effect of HIV sera. Supernatants from HIV sera-treated macrophages were found to significantly enhance (P < 0.01) mesangial cell incorporation of [3H]proline, a marker for synthesis of the matrix component collagen, compared to supernatants from control sera-treated macrophages. These results suggest that HIV sera may directly enhance mesangial cell proliferation and may indirectly increase mesangial cell matrix synthesis by altering macrophage secretory products. These effects may play a role in the development of glomerulosclerosis in patients with HIV infection.
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PMID:Effects of human immunodeficiency virus sera and macrophage supernatants on mesangial cell proliferation and matrix synthesis. 836 79

We recently demonstrated that stimulation of inducible nitric oxide synthase (iNOS) activity reduced the accumulation of collagen and fibronectin in cultured rat mesangial cells. Therefore, we examined whether nitric oxide (NO) influenced the activity of a 72 kDa neutral matrix metalloproteinase by these cells in vitro. Enzyme activity was assessed in a biotin-avidin ELISA and by zymography. Exposure of mesangial cells to the cytokines, interferon (IFN)-gamma and lipopolysaccharide (LPS), increased gelatinolytic activity by 325 +/- 60% (P < 0.025). Co-incubation with 20 mM L-arginine caused a further increase in matrix metalloproteinase levels. Addition of L-NAME, an inhibitor of iNOS, reversed the IFN-gamma/LPS-induced rise in gelatinolytic activity. Incubation with the exogenous NO donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP), resulted in a dose dependent increase in metalloproteinase activity (P < 0.01). The NO-induced changes in metalloproteinase activity were also demonstrable by zymography. These data indicate that NO modulates the activity of a 72 kDa neutral matrix metalloproteinase and suggest that altered NO production may contribute to the development of glomerulosclerosis and tubulointerstitial fibrosis in chronic renal disease states.
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PMID:Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. 857 77

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other molecules. These events accelerate the process of chronic rejection.
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PMID:Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts. 883 48

Glomerulosclerosis is the final outcome of a number of different causes of glomerular injury, during which the structures of the glomerulus are obliterated by extracellular matrix. Accumulating evidence suggests that infiltrating macrophages play a pivotal role in the progression to glomerulosclerosis. The present study defines the role played by macrophages at both cellular and molecular levels in the initiation of the sclerotic process in cultured rat mesangial cells. Macrophage-conditioned medium (MPCM) generated from thioglycollate-elicited, lipopolysaccharide-stimulated macrophages upregulated mesangial cell fibronectin production in a dose- and time-dependent manner, independently of cell proliferation. Immunoprecipitation of metabolically labeled 35S-fibronectin confirmed that the matrix protein was synthesized de novo. The genes for fibronectin and the matrix proteins laminin and collagen IV were also found to be upregulated 2.86 +/- 0.24-, 4.94 +/- 0.17-, and 3.03 +/- 0.31-fold over controls, respectively (P < 0.001). Macrophage modulation of matrix turnover was suggested by an upregulation of both transin and tissue inhibitor of metalloproteinase-1 gene transcription. Transforming growth factor (TGF) beta1, platelet-derived growth factor, tumor necrosis factor (TNF) alpha, or interleukin (IL)-1beta could not be detected in the MPCM per se; however, TGFbeta1 and platelet-derived growth factor AB were found to be secreted into mesangial cell culture supernatants. Secretion was augmented 1.69 +/- 0.16- and 2.28 +/- 0.28-fold, respectively (both P < 0.001), in response to MPCM. Northern blot analysis demonstrated that protein secretion had been preceded by upregulation of the genes for these cytokines (2.2 +/- 0.4-fold [P < 0.001] and 5.7 +/- 1.2-fold [P < 0.004], respectively). Incubation of MPCM with either neutralizing antibody or the growth factor receptor antagonist suramin demonstrated that TGFbeta1 played a significant, although minor, role in MPCM-stimulated fibronectin production. In conclusion, this study provides compelling evidence for a direct role of macrophages in the progression to glomerulosclerosis.
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PMID:Macrophages promote prosclerotic responses in cultured rat mesangial cells: a mechanism for the initiation of glomerulosclerosis. 933 80

To investigate whether MCP-1, CINC, RANTES, osteopontin and ICAM-1 mRNA could be induced in cultured rat mesangial cells by interleukin-1beta(IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS), and whether MCP-1 and CINC gene expression could be modulated by dexamethasone, Northern blot assays were performed. IL-1beta induced MCP-1, CINC, RANTES and ICAM-1 gene expression in a time dependent manner. IL-1beta-induced MCP-1, CINC and ICAM-1 mRNA amount were maximal at 3 hours exposure around 14.5, 15.7, 2.2 folds increase and IL-1beta-induced RANTES mRNA at 24 hours around 2.0 folds. TNF-alpha and LPS also induced MCP-1 and ICAM-1 gene expression. TNF-alpha also induced RANTES gene expression but LPS did not. On the other hand, IL-1beta, TNF-alpha and LPS had little effect on osteopontin gene expression but fetal calf serum could increase osteopontin mRNA. Dexamethasone suppressed the IL-1beta-induced MCP-1 and CINC mRNA. These results suggest that, through these gene expressions, mesangial cells are able to communicate directly or indirectly with macrophages or neutrophils, which may lead to glomerulosclerosis.
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PMID:Chemokines, osteopontin, ICAM-1 gene expression in cultured rat mesangial cells. 961 Jun 17

Mice transgenic for bovine growth hormone (GH) develop progressive glomerulosclerosis. However, the proximal signaling events that lead to increased matrix deposition in this pathologic condition are still unclear. Components of the L-arginine metabolic pathway, especially inducible nitric oxide (NO) synthase (iNOS), ornithine aminotransferase (OAT), and ornithine decarboxylase (ODC), have been associated with glomerular scarring. In this study, mesangial cells were treated with GH, and the expression of iNOS, ODC, and OAT was determined using reverse transcription-PCR. In addition, nitrite accumulation in the conditioned media of mesangial cell cultures was measured in the presence or absence of GH. The findings revealed that GH increased iNOS transcript levels in a dose-dependent manner, with the highest levels being attained at GH concentrations of 20 to 50 ng/ml. The GH-induced increase in iNOS transcript levels was accompanied by a significant increase in nitrite concentrations in conditioned media, which was blocked by the addition of L-N(G)-monomethylarginine. The effect of GH (50 ng/ml) in eliciting nitrite production was as potent as that of bacterial lipopolysaccharide (10 microg/ml). The expression of OAT and ODC, in contrast, was not altered at any of the GH concentrations tested. GH receptor mRNA was also expressed by mesangial cells, independently of the GH concentration present in the cell culture medium. These data indicate that GH may interact with its receptor to regulate the L-arginine/NO pathway in mesangial cells, by directly modulating iNOS expression and NO production, without altering the arginase/OAT/ODC pathway.
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PMID:Growth hormone increases inducible nitric oxide synthase expression in mesangial cells. 1090 55

Macrophage infiltration of the kidney is a prominent feature associated with the severity of renal injury and progressive renal failure. To determine the influence of macrophages in renal disease models in the absence of endogenous T and B cells, we performed adoptive transfer of macrophages into severe combined immunodeficient (SCID) mice. In this study, macrophages were isolated from the spleens of BALB/c mice and stimulated with lipopolysaccharide to induce classically activated M1 macrophages or with interleukin-4 (IL-4) and IL-13 to induce alternatively activated M2 macrophages. These macrophages were then infused into SCID mice with adriamycin nephropathy; an in vivo model of chronic inflammatory renal disease analogous to human focal segmental glomerulosclerosis. Mice infused with M1 macrophages had a more severe histological and functional injury, whereas M2 macrophage-induced transfused mice had reduced histological and functional injury. Both M1 and M2 macrophages localized preferentially to the area of injury and maintained their phenotypes even after 4 weeks. The protective effect of M2 macrophages was associated with reduced accumulation and possibly downregulated chemokine and inflammatory cytokine expression of the host infiltrating macrophages. Our findings demonstrate that macrophages not only act as effectors of immune injury but can be induced to provide protection against immune injury.
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PMID:Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. 1765 30

Glomerulosclerosis is a common disorder in many types of chronic kidney diseases. Previous studies have shown that glomerular mesangial cells (MCs) play an important role in the pathogenesis of glomerulosclerosis. The ability of saikosaponin-d (SSd) to reduce the damage of kidney in progressive glomerulosclerosis has been demonstrated. In this study, the effects of saikosaponin-d on MC proliferation and synthesis of extracellular matrix proteins were investigated. Rat MCs were isolated from Wistar rats and cultured in Dulbecco's modified Eagle's medium. MCs were challenged with lipopolysacchorides and incubated with different concentrations of SSd. Cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and lactate dehydrogenase assays. Type IV collagen, fibronectin, and TGF-beta1 in the conditioned medium were measured. The expression of cyclin-dependent kinase 4, c-Jun, and c-Fos was determined by immunohistochemistry. At a concentration of 4 microg/mL or lower, SSd inhibited MC proliferation but did not cause cell death. SSd also inhibited lipopolysaccharide-induced secretion of type IV collagen, fibronectin, and TGF-beta1 in MCs. Additionally, SSd reduced the expression of CDK4, c-Jun, and c-Fos in MCs. We conclude that SSd inhibited MC proliferation and synthesis of extracullular matrix proteins through the downregulation of the CDK4, c-Jun, and c-Fos genes.
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PMID:Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteins. 1753 96


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