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: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibodies against RNA polymerase I were detected in plasma and kidney eluates of NZB/W mice. Plasma concentrations of the antibodies were the highest in mice with incipient nephritis and the lowest in mice with progressive nephritis. Mice with attenuated nephritis due to immunosuppressive therapy had intermediate plasma concentrations of the antibodies. The specific concentrations (ng/microgram IgG) of anti-RNA polymerase I antibodies in kidney eluates were significantly (10- to 70-fold) greater than the corresponding plasma concentrations. These results indicated that the decreased plasma concentration of the antibodies in mice with more advanced disease was at least partially due to selective concentration of anti-RNA polymerase I antibodies in the kidneys. The degree of this selective concentration was directly proportional (R2 = 0.9962) to the severity of renal disease, as reflected by the concentration (microgram/g tissue) of IgG eluted from the kidneys. The concentration (microgram/g tissue) of anti-RNA polymerase I eluted from the kidneys also was increased in mice with more severe renal disease. Further, the extent of this increase was greater than that of total IgG, again suggesting that anti-RNA polymerase I antibodies had been selectively concentrated in the kidneys. These findings are strongly suggestive of an important role for the RNA polymerase I/anti-RNA polymerase I antibody system in the pathogenesis of murine lupus nephritis.
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PMID:Anti-RNA polymerase I antibodies: potential role in the induction and progression of murine lupus nephritis. 355 5

During the past two decades, the essentiality of zinc for man has been established. Deficiency of zinc in man due to nutritional factors and several diseased states has been recognized. High phytate content of cereal proteins decreases availability of zinc; thus the prevalence of zinc deficiency is likely to be high in a population subsisting mainly on cereal proteins. Alcoholism is known to cause hyperzincuria and thus may play a role in producing zinc deficiency in man. Malabsorption, cirrhosis of the liver, chronic renal disease and other chronically debilitating diseases may similarly induce zinc deficiency in human subjects. A severe deficiency of zinc has recently been recognized to occur in patients with sickle cell anemia and a beneficial effect of zinc therapy in such patients has been reported. Growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy and delayed wound healing are some of the manifestations of chronically zinc-deficient human subjects. Taste abnormalities, correctable with zinc supplementation, have been observed in uremic subjects. Recently, abnormal dark adaptation related to zinc deficiency in patients with cirrhosis of the liver and sickle cell disease has been reported. In severely zinc-deficient patients, dermatological manifestations, diarrhea, alopecia, mental disturbances and intercurrent infections predominate and if untreated the condition becomes fatal. Zinc deficiency is known to affect testicular functions adversely in man and animals. This effect of zinc is at the end organ level and it appears that zinc is essential for spermatogenesis and testosterone steroidogenesis. Zinc is involved in many biochemical functions. Several zinc metalloenzymes have been recognized in the past decade. Zinc is required for each step of cell cycle in microorganisms and is essential for DNA synthesis. Thymidine kinase, RNA polymerase, DNA-polymerase from various sources and RNA-dependent DNA polymerase from viruses have been shown to be zinc-dependent enzymes. Zinc also regulates the activity of RNase; thus the catabolism of RNA appears to be zinc-dependent. The effect of zinc on protein synthesis may be attributable to its vital role in nucleic acid metabolism. The activities of many zinc-dependent enzymes have been shown to be affected adversely in zinc-deficient tissues. Three enzymes, alkaline phosphatase, carboxypeptidase and thymidine kinase, appear to be most sensitive to zinc restriction in that their activities are affected adversely within three to six days of institution of a zinc-deficient diet to experimental animals.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Zinc deficiency in human subjects. 636 78

The purpose of this article is to review a set of recently obtained data concerning matrix and matrix adhesion molecules in renal disease. Our goal is not to cover the entire topic, but rather to focus on findings obtained with an experimental model for chronic lupus nephritis, evoked in mice by inducing graft-versus-host disease (GVHD). The overall aim of these studies was to investigate the role of adhesion molecules as targets for autoantibodies, in the recruitment of inflammatory cells, and in the accumulation of matrix in kidney disorders. In addition, we set out to discover how matrix proteins in renal diseases differ from normal matrix molecules both quantitatively, in their increased frequency, and qualitatively, in their intramolecular structure. The advances in understanding and methodology described in this review imply a substantial capability for greater insight into the pathogenesis of kidney disease; for making better use of renal biopsies, such as in applying competitive reverse-transcriptase-polymerase chain reaction (RT-PCR) in RNA analysis for matrix; and in developing more effective treatment strategies for patients with kidney disease.
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PMID:Matrix and adhesion molecules in kidney pathology: recent observations. 935 73

There are three classes of RNA polymerase enzyme (RNAPs I, II and III). In systemic sclerosis (SSc), three main groups of anti-RNAP sera have been characterized by radioimmunoprecipitation techniques: anti-RNAP I/III sera, anti-RNAP I/II/III sera, and a group precipitating both RNAP II and topoisomerase I (topo I). Some sera in this third group precipitate the phosphorylated (IIO) form of RNAP II in the absence of the unphosphorylated (IIA) form. Certain other antinuclear antibodies (ANA) have also been detected in anti-RNAP IIO/IIA/topo I and anti-RNAP IIO/topo I sera. In the present study of 155 SSc patients, clinical features of individuals from each of these antibody groups were assessed and compared with those of patients from other autoantibody-defined groups. The anti-RNAP I/II/III antibody specificity was closely associated with the presence of diffuse cutaneous SSc (dc-SSc) (77.8%; cf. remaining group, 12.4%; P < 0.001; relative risk (RR) 6.3). Patients with anti-RNAP I/III antibodies also had an increased incidence of dc-SSc, but this was not significant (42.9%; cf. remainder, 15.7%). Anti-RNAP+ patients had a significantly increased incidence of renal involvement (29.0%, cf. remainder, 11.3%; P < 0.05; RR 2.6), with 40% of anti-RNAP I/II/III patients having renal disease. Meanwhile, the presence of anti-centromere antibodies (ACA) was associated with limited cutaneous SSc (lc-SSc) (100.0%; cf. remainder, 75.3%; P < 0. 005), together with reduced incidences of both renal disease (2.4%, cf. remainder, 22.1%: P < 0.01) and pulmonary fibrosis (21.4%, cf. remainder, 52.3%; P < 0.005; RR 1.9). Anti-topo I antibodies were associated with the presence of pulmonary fibrosis (69.7%; cf. remainder, 32.6%; P < 0.001; RR 2.1). A majority of anti-topo I sera were from lc-SSc patients, regardless of whether anti-topo I antibodies occurred alone (75.0%) or together with anti-RNAP IIO + IIA antibodies (75.0%), and this was similar to the remainder (86. 5%; NS). However, when anti-topo I+ patients were compared with the ACA group, and then with all anti-RNAP I+ patients (37.5% lc-SSc), significant differences were found in the occurrence of dc- versus lc-SSc (P < 0.005 and P < 0.05, respectively). In conclusion, these results confirm that there are three main groups of SSc sera, each characterized by the presence of a mutually exclusive SSc-specific autoantibody (ACA, anti-topo I or anti-RNAP I), and distinguished by patterns of cutaneous involvement and specific clinical features. It appears that, in each of the three groups of SSc patients, distinct pathological processes are occurring, which are responsible for the characteristic symptoms, for the modification of particular autoantigens and, consequently, for the production of particular autoantibodies. Based on these data, together with our previous results, it is further hypothesized that anti-RNAP II antibodies may be produced in the context of two different immune response pathways.
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PMID:Clinical and serological associations with anti-RNA polymerase antibodies in systemic sclerosis. 1044 76

To gain insight into the glomerular capillary repair mechanisms in immunoglobulin A (IgA) nephropathy, we focused on vascular endothelial growth factor (VEGF-A) and nitric oxide (NO). Because abnormal glycosylation of serum IgA has been shown in IgA nephropathy, we examined whether VEGF-A and NO production by mesangial cells (MCs) could be modulated by aberrantly glycosylated (desialylated or degalactosylated) IgA. VEGF-A and NO synthase (NOS) gene expression were examined by reverse-transcriptase polymerase chain reaction (RT-PCR) or Northern blot analysis, and VEGF-A peptide, by capture enzyme-linked immunosorbent assay and NOS activity as production of tritium ([(3)H]) citrulline from [(3)H] arginine. Semiquantitative densitometric analysis of RT-PCR experiments showed a significant downregulation of VEGF-A messenger RNA (mRNA) in MCs incubated with aberrantly glycosylated IgA. This resulted in decreased release of VEGF-A in culture medium (P: < 0. 01). NOS activity and inducible NOS (iNOS) mRNA were enhanced by aberrantly glycosylated IgA (both P: < 0.01). No modulation of constitutive NOS mRNA was found. The depression of the VEGF-A production induced by aberrantly glycosylated IgA was mediated by NO because it was completely reversed by the NOS inhibitor, N:omega-nitro-L-arginine methyl ester. The NO donor, sodium nitroprusside, induced a bimodal modulation of VEGF; although low concentrations (0.0001 nmol/L) increased VEGF-A synthesis, greater concentrations (1,000 nmol/L) depressed it. In conclusion, we report negative control of VEGF-A synthesis in MCs by aberrantly glycosylated IgA, mediated by enhanced iNOS activity. We speculate that both increased iNOS activity and depressed VEGF-A synthesis might have a role in impairing vascular repair and favor sclerosis in IgA nephropathy.
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PMID:Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. 1109 49

Progression of renal disease is closely correlated to the degree of renal interstitial fibrosis, and evidence is increasing that epithelial cells of the renal proximal tubule (PTCs) may contribute to its pathogenesis. Such cytokines as basic fibroblast growth factor (FGF-2) have been implicated in progressive renal injury, and we previously showed that PTCs are a source of this cytokine. FGF-2 is characterized by its high affinity for heparin, and numerous studies have suggested that heparin may modify the progression of renal disease. The current study examined how heparin influenced FGF-2 generation and bioactivity in the human renal epithelial PTC line, HK-2. Incubation of HK-2 cells with heparin led to a dose- and time-dependent increase in FGF-2 concentration in the culture supernatant that was not accompanied by alterations in FGF-2 messenger RNA expression, assessed by reverse-transcriptase polymerase chain reaction and Northern analysis. The heparin-induced increase in FGF-2 concentration was accompanied by a decrease in the amount of FGF-2 bound to the extracellular matrix, although this accounted for only a small proportion of the total FGF-2 generated. Induction of FGF-2 by 2-O-desulfated heparin, together with a reduction in total cell-associated FGF-2 and anti-FGF-2 antibody binding to fixed permeabilized cells after the addition of heparin, suggested that the FGF-2 released was mainly derived from a preformed intracellular source. That FGF-2 was predominantly derived from an intracellular pool was also confirmed by pulse chase experiments. The addition of heparin resulted in the generation of bioinactive FGF-2, judged by in vitro fibroblast proliferation. Conversely, heparitinase treatment of supernatant samples from heparin-treated cells and the addition of 2-O-desulfated heparin resulted in the generation of active FGF-2, suggesting that the generation of bioinactive FGF-2 was related to binding of FGF-2 by extracellular heparin after its release from cells. These data show that heparin depletes both the cell and surrounding matrix of FGF-2 and suggest that FGF-2 released from cells was mainly derived from a preformed intracellular source. Furthermore, FGF-2 released from epithelial PTCs after the application of heparin was bioinactive. This likely resulted from released FGF-2 binding to an excess of extracellular heparin. Results presented here therefore suggest a mechanism by which heparin, through its effect on depletion of matrix and cells of FGF-2 and its generation in an inactive form, may influence progressive renal interstitial fibrosis.
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PMID:Regulation of renal proximal tubular epithelial cell fibroblast growth factor-2 generation by heparin. 1153 94

Reflux nephropathy (RN) is a major cause of end-stage renal failure in children and young adults. Intercellular adhesion molecule-1 (ICAM-1), a cell surface glycoprotein, has a role in the regulation of interaction among immune cells. It has been demonstrated that increased levels of tubular ICAM-1 correlate with an extent of tubular damage in diabetic nephropathy. We hypothesized that ICAM-1 local synthesis is altered in reflux nephropathy and therefore designated this study to investigate ICAM-1 expression in RN. The kidney specimens from six patients with severe reflux nephropathy secondary to primary vesicoureteral reflux were obtained at the time of nephrectomy. Control materials included normal kidney specimens obtained from three adult patients during partial nephrectomy for an incidentaloma. Fluorescent immunohistochemistry was carried out using monoclonal antibodies to ICAM-1 utilizing confocal laser scanning microscopy. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to evaluate the relative amount of ICAM-1. In the control kidneys, there was lack of ICAM-1 immunoreactivity in the interstitium and proximal tubules and moderate immunoreactivity in the glomerulus. In the refluxing kidney there was strong ICAM-1 immunoreactivity in the glomerulus, interstitium and proximal tubules. The RT-PCR showed strong ICAM-1 mRNA expression in the refluxing kidneys and absent or weak ICAM-1 expression in the controls. Our findings of increased expression of ICAM-1 in the severe reflux nephropathy kidney suggests that ICAM-1 may play a role in the pathogenesis of renal parenchymal damage associated with RN.
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PMID:ICAM-1 expression is upregulated in reflux nephropathy. 1275 65

Since 1984, human immunodeficiency virus-associated nephropathy has been established as a clinical entity that presents with nephrotic syndrome and progressive kidney failure. The pathological description is usually consistent with a collapsing form of focal segmental glomerulosclerosis. Podocytes and renal tubular cells have been proposed as a reservoir for the human immunodeficiency virus. This nephropathy is the third leading cause of end-stage renal disease in the population of African descent. It is documented that highly active antiretroviral therapy (HAART) successfully reverses or at least controls nephropathy in HIV-positive patients. The success of the treatment of HIV nephropathy now poses 2 problems to nephrologists: (1) an increased population of HIV-positive patients with chronic kidney disease not yet on dialysis and (2) potential nephrotoxicity of antiretroviral medications as well as medications used to treat opportunistic infections. HAART is defined by the combination of 2 reverse transcriptase inhibitors with a protease inhibitor or 3 reverse-transcriptase inhibitors. Many of these antiretrovirals have well-defined nephrotoxic effects. The objective of this text is to review data pertaining to some of the most common antiretrovirals (ARTs) and include information regarding nephrotoxicity of the medications frequently used to combat opportunistic infections. ARTs included in the review are (1) nucleoside reverse-transcriptase inhibitors (zidovudine and didanosine), (2) nucleotide reverse transcriptase inhibitors (adefovir and tenofovir), (3) the protease inhibitors (indinavir and saquinavir), and (4) the HIV fusion inhibitors.
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PMID:Nephrotoxicity as a complication of antiretroviral therapy. 1681 36

ADAM19 (a disintegrin and metalloproteinase 19) is involved in cell-cell and cell-matrix interactions and tumor necrosis factor (TNF)-alpha shedding. We studied ADAM19 in chronic allograft nephropathy (CAN) nephrectomies and in normal human kidneys. Reverse transcriptase (RT) PCR revealed an upregulation of ADAM19 mRNA in CAN when compared with control kidneys (p = 0.002). Using RNA in situ hybridization (ISH), we detected moderate ADAM19 mRNA expression in vascular smooth muscle cells (SMCs) and distal tubuli of control kidneys. In CAN, massive ADAM19 expression was detected in SMCs, distal tubuli, glomerular sclerotic lesions and inflammatory CD4+ cells. To determine whether ADAM19 is specifically related to CAN, we studied transplant biopsies with and without CAN, acute rejection and non-transplant-related kidney diseases: interstitial fibrosis (IF), interstitial atrophy, glomerular fibrosis and interstitial inflammation. In various renal structures, ADAM19 mRNA was significantly higher in CAN when compared with renal allografts without CAN or acute rejection. ADAM19 expression in renal endothelium was significantly higher in acute rejection when compared with renal allografts without CAN. When compared to CAN, ADAM19 was expressed to a similar extent in non-transplant-related interstitial and glomerular fibrosis, interstitial atrophy and inflammation. Although these observational data do not establish a cause and effect relationship, ADAM19 may have a modulatory role in the dysfunctional renal allograft state.
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PMID:Upregulation of ADAM19 in chronic allograft nephropathy. 1682 70

The interleukin-1 receptor antagonist (IL1RN or IL-1Ra) is a natural antagonist of IL-1-beta. Using IL1RN as a possible marker in patients with systemic lupus erythematosus (SLE), we evaluated whether uIL1RN single nucleotide polymorphisms (SNPs) were associated with the pathogenesis of SLE in Taiwanese, and specifically whether IL1RN (rs315952) was significantly associated with end-stage renal disease. We examined IL1RN isoform expression patterns in patients with SLE to determine whether the expressions play a role in the pathogenesis of SLE. Both case-control and family-based association studies were used. For the case-control study, 104 patients with SLE and 97 normal controls were recruited, and for the family-based study, 11 families with SLE without renal disorder were recruited from the 104 patients with SLE. Eight IL1RN SNPs (rs2234678, rs2234679, rs315951, rs315952, rs419598, rs432014, rs447713, and rs451578) were selected for the family-based study. Reverse-transcriptase-polymerase chain reaction (RT-PCR) was used to determine the expression pattern of each isoform. Our results showed that IL1RN (rs315952) was significantly associated with SLE in patients without renal disorder in the family-based study, after disease stratification, but was not significantly associated with SLE in the case-control study. In the family-based study, the haplotype of IL1RN (AGCCTTAG) was significantly associated with SLE (chi2 = 11.714, P < 0.001). Using RT-PCR to determine the expression pattern of the IL1RN isoforms, we found different expression patterns between normal controls and patients with SLE, with an addition of IL1RN isoform4 or the low expression of IL1RN isoform1. We concluded that IL1RN and its isoforms were involved in the pathogenesis of SLE.
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PMID:The different expression patterns of interleukin-1 receptor antagonist in systemic lupus erythematosus. 1717 40


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