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)

We have isolated an ADP-ribosylation factor (ARF) gene from the human malarial parasite, Plasmodium falciparum. The gene (P. falciparum arf1) has four introns and the exons encode a protein of 181 amino acids with high similarity to the mammalian class I ARF proteins 1-3 (> or = 74% amino acid identity). Southern hybridization suggests there is at least one additional arf in the P. falciparum genome. Northern analysis identified a single P. falciparum arf1 mRNA of 1.8 kb in the asexual blood stage form of the parasite. The P. falciparum arf1 mRNA levels are developmentally regulated, reaching a maximum during nuclear division towards the end of the intraerythrocytic cycle. P. falciparum arf1 cDNA was isolated by reverse-transcriptase polymerase chain reaction and used to express a recombinant protein in Escherichia coli. Recombinant P. falciparum ARF1 protein was purified with stoichiometric amounts of bound GDP, although intrinsic guanose triphosphatase activity of the protein could not be detected. The protein stimulated cholera-toxin-catalyzed ADP-ribosyltransferase activity in a reaction that was dependent upon the addition of both dimyristoylglycerophosphocholine and cholate. The protein bound GTP with first-order kinetics with an apparent rate constant, k', of 0.0145 (+/- 0.0019) min-1. These results suggest that P. falciparum ARF1 is a member of the class 1 ARF family and provide additional evidence for the existence of a classical secretory pathway in P. falciparum.
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PMID:Isolation, expression and characterization of the gene for an ADP-ribosylation factor from the human malaria parasite, Plasmodium falciparum. 895 60

We describe the use of antibodies to RNA polymerase III in the diagnosis of scleroderma in 2 patients who presented with renal crisis without other clinical features of the condition. Both presented with accelerated hypertension, rapidly progressive acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. One patient developed digital infarcts in the course of his initial illness. Neither showed evidence of skin thickening at presentation. Nailfold capillaroscopy was normal in one patient and showed capillary dropout in the other. Renal biopsy showed findings consistent with thrombotic microangiopathy and both had anti-RNA polymerase III antibodies.
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PMID:Anti-RNA polymerase III antibodies in the diagnosis of scleroderma renal crisis sine scleroderma. 1055 16

Acute renal failure in association with microangiopathic hemolytic anemia and the pathological finding of thrombotic microangiopathy may occur in a number of conditions including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and systemic sclerosis. Distinguishing between these conditions on clinical grounds may be difficult, and further investigations, including serological tests, are normally helpful. We present a patient who was treated with 5 doses of monthly carboplatin chemotherapy for stage IIb ovarian carcinoma and who subsequently developed acute renal failure and microangiopathic hemolysis together with some cutaneous features of systemic sclerosis. Initial serological tests, including anti-nuclear antibody titers measured using rat hepatocytes, were normal, and renal biopsy showed features of microangiopathic hemolysis, fibrinoid change, patchy tubular atrophy, and concentric intimal proliferation. A clinical diagnosis of diarrhea-negative hemolytic uremic syndrome was made and she was treated with plasma exchange and fresh frozen plasma infusion. However, she remained dialysis-dependent. Several weeks later she died following a cardiac arrest. Post-mortem examination revealed medial hypertrophy, concentric intimal proliferation, and thrombi within the small arteries of the kidneys and lungs. Subsequent results from tests taken at the time of her presentation with acute renal failure revealed a normal von Willebrand factor qualitative distribution, and a positive anti-nuclear antibody titer (using a human cell line) in association with positive autoantibodies to RNA polymerase types I, II, and III. Taken together, the clinical, laboratory, and post-mortem findings were suggestive of a diagnosis of systemic sclerosis. We discuss the differential diagnoses, and the associations between these and malignancy and chemotherapy. Finally, we consider the serological tests used for the diagnosis of systemic sclerosis that were, in this case, initially misleading.
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PMID:Renal failure due to scleroderma with thrombotic microangiopathy developing in a woman treated with carboplatin for ovarian cancer. 1242 90

A 37-year-old Belgian patient presented with acute nephropathia epidemica (NE) shortly after a camping holiday in southern France. Unusual symptoms were initial noncardiogenic lung involvement, followed by severe acute renal failure, acute acalculous cholecystitis, presence of immunoblasts in the bone marrow, and hemolytic anemia, presenting as hemolytic uremic syndrome. Positive immunoglobulin (Ig) A and rising IgG titers against Puumala hantavirus (PUUV) were detected, but IgM remained negative on days 8 and 20. The results of reverse-transcriptase-polymerase chain reaction performed on day 8 were positive for PUUV. This is the first report of an iatrogenically IgM-negative hantavirus case due to the selective removal of heavy-weight molecules during plasma exchange via the centrifugation technique. This is also the first report of proven NE from the Mediterranean part of France.
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PMID:Plasma exchange-associated immunoglobulin m-negative hantavirus disease after a camping holiday in southern france. 1515 69

Tenofovir disoproxil fumarate, a prodrug of tenofovir, is a potent nucleotide analogue reverse-transcriptase inhibitor with activity against human immunodeficiency virus (HIV). Although initially thought to be relatively safe with regards to nephrotoxic effects compared to its class drugs-adefovir and cidofovir, several cases of acute renal failure and proximal tubule dysfunction have been described in the last few months. We report another patient who developed Fanconi syndrome while on tenofovir. Her condition improved on discontinuation of the drug. We also review the literature of all patients who have developed Fanconi syndrome on tenofovir.
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PMID:Acute renal failure and Fanconi syndrome in an AIDS patient on tenofovir treatment--case report and review of literature. 1603 54

Acute renal failure (ARF) sensitizes the kidney to endotoxin (LPS)-driven production of cytokines and chemokines. This study assessed whether this LPS hyperresponsiveness exists at the genomic level. Three heterogeneous mouse models of ARF were studied: Maleate nephrotoxicity, unilateral ureteral obstruction, and LPS preconditioning. In all cases, LPS was injected approximately 18 h after injury was induced, and over the next 0 to 90 min, RNA polymerase II recruitment to the genome at three LPS-responsive genes (TNF-alpha, monocyte chemoattractant-1 [MCP-1], and heme oxygenase-1 [HO-1]) was assessed by chromatin immunoprecipitation. LPS hyperresponsiveness was noted in each model, measured by exaggerated increases in TNF-alpha and MCP-1 mRNA (approximately two to 10 times higher than LPS-injected controls). Corresponding increases in the recruitment of RNA polymerase II to the TNF-alpha and MCP-1 genes were observed, and increased trimethylation of histone 3 lysine 4 (H3K4m3) at these sites may have played a role in this recruitment. Conversely, recruitment of RNA polymerase II to the HO-1 gene was suppressed ("tolerance"), and no increase in H3K4m3 was observed at HO-1 exons. The ARF-induced changes in mRNA did not correlate with mRNA stability, suggesting the mechanistic importance of RNA polymerase II-mediated transcriptional events. In conclusion, LPS hyperresponsiveness after ARF is likely mediated at the genomic level, possibly by H3K4m3.
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PMID:Endotoxin mediates recruitment of RNA polymerase II to target genes in acute renal failure. 1841 19

Scleroderma renal crisis (SRC) occurs in 5-10% of SSc patients, who may present with an abrupt onset of hypertension, acute renal failure, headaches, fevers, malaise, hypertensive retinopathy, encephalopathy and pulmonary oedema. Patients at greatest risk of developing SRC are those with diffuse cutaneous or rapidly progressive forms of SSc, and treatment with a recently commenced high dose of corticosteroid. Laboratory tests may demonstrate hypercreatinaemia, microangiopathic haemolytic anaemia (MAHA), thrombocytopaenia and hyperreninaemia. Renal crisis is also linked to a positive ANA speckled pattern, antibodies to RNA polymerase I and II, and an absence of anti-centromere antibodies. Early, aggressive treatment with angiotensin-converting enzyme inhibitors has improved prognosis in SRC, although 40% of the patients may require dialysis, and mortality at 5 yrs is 30-40%. Median time to recovery is 1 yr, and typically occurs within 3 yrs. Prognosis is worse for males, but may not be related to corticosteroid use, presence of MAHA or severity of renal pathology. Modification of endothelin over-activity, which is implicated in the pathogenesis of SRC, may offer a future therapeutic approach.
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PMID:Renal complications and scleroderma renal crisis. 1948 21

Inflammatory cytokines are evoked by acute kidney injury (AKI) and may contribute to evolving renal disease. However, the impact of AKI-induced uremia on proinflammatory (e.g., TNF-alpha, MCP-1, TGF-beta1) and anti-inflammatory (e.g., IL-10) cytokine gene expression remains unknown. This study was undertaken to gain some initial insights into this issue. CD-1 mice were subjected to left renal ischemia-reperfusion (I/R) in the absence or presence of uremia (+/- right ureteral transection). TNF-alpha, MCP-1, TGF-beta1, and IL-10 mRNAs, cytokine protein levels, and RNA polymerase II (Pol II) recruitment to these genes were assessed. Renal cytokine mRNA levels were also contrasted with unilateral vs. bilateral renal parenchymal damage (I/R or ureteral obstruction). Potential effects of uremia on cytokine mRNAs in the absence of parenchymal renal damage [bilateral ureteral transection (BUTx)] were sought. Finally, the impact of simulated in vitro uremia (HK-2 tubular cells exposed to peritoneal dialysate from uremic vs. normal mice) on cytokine mRNA and microRNA profiles was assessed. Uremia blunted TNF-alpha, MCP-1, and TGF-beta1 mRNA increases in all three in vivo parenchymal acute renal failure models. These results were paralleled by reductions in cytokine protein levels and Pol II recruitment to their respective genes. Conversely, uremia increased IL-10 mRNA, both in the presence and absence (BUTx) of parenchymal renal damage. The uremic milieu also suppressed HK-2 cell proinflammatory cytokine mRNA levels and altered the expression of least 69 microRNAs (P < 0.0001). We conclude that both pro- and anti-inflammatory cytokine gene expressions are influenced by uremia, with a potential predilection toward an anti-inflammatory state. Changes in gene transcription (as reflected by Pol II recruitment), and possible posttranscriptional modifications (known to be induced by microRNAs), are likely involved.
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PMID:Uremia impacts renal inflammatory cytokine gene expression in the setting of experimental acute kidney injury. 1965 11

Hantaviruses are rodent-borne viruses capable of causing human disease. The Seoul virus is a hantavirus that causes hemorrhagic fever with renal syndrome in East Asia. To our knowledge, we report the first domestically acquired case of hemorrhagic fever with renal syndrome caused by the Seoul virus, confirmed by serology testing, reverse-transcriptase polymerase chain reaction, and nucleotide sequence analysis. The patient presented with myalgias and fever, and developed acute renal failure.
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PMID:Domestically acquired seoul virus causing hemorrhagic fever with renal syndrome-Maryland, 2008. 1984

Rhabdomyolysis (Fe)-induced acute renal failure (ARF) causes renal inflammation, and, with repetitive insults, progressive renal failure can result. To gain insights into these phenomena, we assessed the impact of a single episode of glycerol-induced rhabdomyolysis on proinflammatory/profibrotic [TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 (TGF-beta1)] gene expression and the time course of these changes. CD-1 mice were studied 1-7 days after glycerol injection. Normal mice served as controls. RNA polymerase II (Pol II) binding to the TNF-alpha, MCP-1, and TGF-beta1 genes, "gene-activating" histone modifications [histone 3 lysine 4 (H3K4) trimethylation (H3K4m3) and histone 2 variant H2A.Z], and cognate mRNA levels were assessed. Results were contrasted to changes in anti-inflammatory heme oxygenase-1 (HO-1). Glycerol produced severe ARF (blood urea nitrogen approximately 150-180 mg/dl) followed by marked improvement by day 7 (blood urea nitrogen approximately 40 mg/dl). Early increases in TNF-alpha, MCP-1, and TGF-beta1 mRNAs, Pol II gene binding, and H3K4m3/H2A.Z levels were observed. These progressed with time, despite resolution of azotemia. Comparable early HO-1 changes were observed. However, HO-1 mRNA normalized by day 7, and progressive Pol II binding/histone alterations did not occur. Fe-mediated injury to cultured proximal tubule (HK-2) cells recapitulated these in vivo results. Hence, this in vitro model was used for mechanistic assessments. On the basis of these studies, it was determined that 1) the H3K4m3/H2A.Z increases are early events (i.e., they precede mRNA increases), 2) subsequent mRNA elevations reflect transcription, not mRNA stabilization (actinomycin D assessments), and 3) increased transcription, per se, helps sustain elevated H2A.Z levels. We conclude that 1) Fe/glycerol-induced tubular injury causes sustained proinflammatory gene activation, 2) decreasing HO-1 expression, as reflected by mRNA levels, may facilitate this proinflammatory state, and 3) gene-activating histone modifications are early injury events and progressively increase at selected proinflammatory genes. Thus they may help sustain a proinflammatory state, despite resolving ARF.
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PMID:Progressive histone alterations and proinflammatory gene activation: consequences of heme protein/iron-mediated proximal tubule injury. 2003 14


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