Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.
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PMID:Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. 170 82

This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man with human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors.
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PMID:Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. 1209 87

A 14-year-old mixed-breed dog was examined because of severe absolute erythrocytosis (PCV, 70%). Plasma erythropoietin (EPO) concentration was consistently high, even though results of arterial blood gas analyses were normal. Radiography, ultrasonography, urinalysis, and serum biochemical analyses did not reveal any cardiac, pulmonary, or renal abnormalities that could cause the erythrocytosis, and erythrocytosis secondary to inappropriate EPO secretion was diagnosed. The PCV was maintained at approximately 60% by means of periodic phlebotomy, and the dog died of acute renal failure 2 years later. At necropsy, a cecal leiomyosarcoma was identified. Immunohistochemical staining of sections of the tumor revealed intracellular vacuoles containing EPO, and EPO mRNA was detected in the tumor by use of a reverse transcriptase-polymerase chain reaction assay These results suggested that ectopic production of EPO by a cecal leiomyosarcoma was the cause of erythrocytosis in this dog.
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PMID:Secondary erythrocytosis associated with high plasma erythropoietin concentrations in a dog with cecal leiomyosarcoma. 1186 Feb 44

Although nephrotoxicity of cidofovir and adefovir is well established, no renal side effects have been observed yet with tenofovir, which is the third member of this family. The authors report the case of a patient who had Fanconi syndrome, nephrogenic diabetes insipidus, and acute renal failure during treatment with tenofovir, a nucleotide reverse transcriptase inhibitor that recently has been approved by the Food and Drug Administration for treatment of patients infected with human immunodeficiency virus.
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PMID:Fanconi syndrome and renal failure induced by tenofovir: a first case report. 1246 55

Although ischemia remains the leading cause of acute renal failure in humans, there is little information on the expression and activities of gelatinases of kidney glomeruli during ischemia-reperfusion injury. In this study, we used a unilateral ischemia-reperfusion model to investigate the activity and expression of gelatinases in glomeruli during acute ischemia. Unilateral ischemia was induced in rats by vascular clamping (30 min) followed by reperfusion (60 min) and isolation of glomeruli. The activity and expression of gelatinase proteins were determined by gelatin zymography and Western blotting. Gelatinase mRNA levels were evaluated by reverse transcriptase-PCR. Ischemia and reperfusion increased serum creatinine levels, hallmark of acute renal failure. Ischemia induced mRNA and protein MMP-2 expression. There was strong stimulation of MMP-9 mRNA, both forms of dimeric MMP-9, and active monomeric MMP-9. In contrast to TIMP-1 decreasing, TIMP-2 protein and mRNA increased during ischemia. During reperfusion, there was a gradual reversal of the MMP-2 and MMP-9 levels and a strong inhibition of TIMP-1 and TIMP-2 at the protein and mRNA levels. Endocytic receptor LRP was increased during ischemia and returned to normal during reperfusion. Expression of MMP-9 docking receptor CD-44 was increased during reperfusion. Finally, ZO-1, an in vivo MMP-9 substrate, was degraded during ischemia, revealing that MMP-9 upregulated during ischemia was functional. Our data suggest that stimulation of gelatinase activity during ischemia could contribute to glomeruli injury, providing new therapeutic targets for acute renal failure in humans. In contrast, elevated monomeric MMP-9 activity due to TIMP-1 decrease during reperfusion may participate to glomerular recovery.
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PMID:Ischemia-reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli. 1587 Aug 43

Loop diuretics are known to affect renal hemodynamics and possibly gene transcription, but the specific effect of furosemide on renal angiogenesis gene expression after acute ischemia is not known. We utilized an acute renal failure model in rats to test the hypothesis that furosemide improves renal hemodynamics and alters the transcriptional signature of acute ischemic nephropathy. Twenty-four male Sprague-Dawley rats were anesthetized by the intraperitoneal administration of 50 mg/kg urethane. Animals were divided into four groups (n = 6 each): (1) sham-operated group infused with saline; (2) sham-operated group infused with 30 microg/kg/hr furosemide (equivalent to a human dosage of 2 mg/hr); (3) unilateral renal ischemia (1 hr, left renal artery cross-clamping) followed by 6 hr of reperfusion; and (4) renal ischemia/ reperfusion (I/R) with furosemide. Renal artery blood flow (RBF), renal cortical perfusion (RCP), and renal corticomedullary tissue oxygen tension (PO2) were recorded throughout. Following 6 hr of reperfusion, left kidney RNA was used to probe microarrays. Gene expression was measured as percent positive control and confirmed using reverse transcriptase polymerase chain reaction. Physiologic data were analyzed by calculating area under the curve, and gene expression data were compared by using multiple analysis of variance with Tukey's post-hoc tests. Furosemide significantly increased RBF (P < 0.05) and PO2 (P < 0.05) in postischemic kidneys. Furosemide attenuated nine of the 13 ischemia-induced and 41 of 78 ischemia-suppressed angiogenesis-related genes. This attenuation was statistically significant (P < 0.05) for 17 I/R injury-suppressed genes. Data from this rat model of ischemic nephropathy suggest that furosemide improves renal hemodynamics and attenuates ischemia-related changes in gene expression.
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PMID:Effect of furosemide infusion on renal hemodynamics and angiogenesis gene expression in acute renal ischemia/reperfusion. 1652 16

The pathogenesis of renal ischemia/reperfusion (I/R) injury involves activating several signal transduction cascade systems in endothelial cells. Sphingosine 1-phospate (S1P) maintains endothelial cell integrity and inhibits lymphocyte egress via the specific S1P(1) receptor, and may play a role in reducing ischemic renal injury. We examined the protective effects of a newly identified S1P(1)-selective agonist, SEW2871, on mouse renal I/R injury. Kidneys were harvested 1-4 days after I/R injury for histopathology, immunofluorescence studies, and quantitative real-time reverse transcriptase-polymerase chain reaction analyses to assess the change in gene expression profiles of inflammation-associated cytokines and adhesion molecules. SEW2871 improved renal function with a 40% reduction in plasma creatinine levels (P<0.01) and a significant reduction in tubular necrosis scores (I/R only: 4.3+/-0.2 vs I/R+SEW2871: 2.5+/-0.4, P<0.05) 24 h after ischemia. These changes were accompanied by 69% reduction in circulating lymphocytes, and 77 and 66% reduction in infiltrating neutrophils and macrophages in renal outer medulla, respectively (all P<0.01). The mRNA abundance of tumor necrotic factor-alpha (TNF-alpha), P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) was markedly increased by I/R injury (3.5-, 4.1-, 3.5-, and 4.8-folds, respectively, all P<0.05 vs sham). SEW2871 treatment partially reversed the upregulation of TNF-alpha, P-selectin, and ICAM-1 (47, 59, 54%, respectively, vs I/R control: 100%, all P<0.05). The reduction in protein expression of TNF-alpha, P-selectin, and ICAM-1 was further confirmed with immunofluorescence studies. These results suggest that SEW2871 ameliorates renal I/R injury by inhibiting lymphocyte egress and reducing pro-inflammatory molecules. This new class of renoprotective agent shows promise as a novel approach in preventing/treating ischemic acute renal failure.
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PMID:S1P(1)-selective agonist, SEW2871, ameliorates ischemic acute renal failure. 1657 8

Tenofovir, a new nucleotide reverse transcriptase inhibitor that has good antiviral activity against drug-resistant strains of HIV, is structurally similar to cidofovir and adefovir and seems to be less nephrotoxic. Nephrotoxicity of cidofovir and adefovir is well established and they have been associated with increase for acute renal insufficiency due to tubular toxicity, possibly induced via mitochondrial deplection. Tenofovir has little mithocondrial toxicity in in vitro assays and early clinical studies. However some cases of renal tubular dysfuntion and renal failure related to tenofovir treatment have been published recently. Increased plasma concentrations of didanosine were observed after the adition of tenofovir and protease inhibitors can interact with the renal transport of organic anions leading to proximal tubular intracellular accumulation of tenofovir, yield Fanconi syndrome-type tubulopathy. We present a case in wich acute renal failure and proximal tubular dysfunction developed after therapy with tenofovir in a patiente with HIV who had suffered from complications of didanosine treatment. Although nephrotoxicity certainly occurs much less frequently with tenofovir that it does with other nuclotide analogues, use of tenofovir by patients with underlying renal disfuntion, for longer durations and/or associated with didanosine or lopinavir-ritonavir, might be associated with renal toxicity. Patients receiving tenofovir must be monitored for sings of tubulopathy with simple tests such us glycosuria, phosphaturia, proteinuria, phosphoremia and renal function, as well as assessment for signs of mithocondrial toxicity when a nucleoside analogue is being administered, and therapy should be stopped to avoid the risk of definitive renal failure.
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PMID:[Acute renal failure and proximal renal tubular dysfuntion in a patient with acquired immunodeficiency syndrome treated with tenofovir]. 1711 9

Tenofovir is an acyclic nucleotide analogue reverse transcriptase inhibitor that is commonly prescribed as part of a highly active antiretroviral therapy (HAART) regimen in HIV-infected patients. Although it is generally well tolerated, renal insufficiency has been associated with its use. We report a biopsy-proven case of acute renal failure that developed within weeks of initiating a HAART regimen containing tenofovir, and review the literature with specific attention to cases of renal failure occurring within 8 weeks of tenofovir initiation. Our patient developed renal insufficiency within 3 weeks of initiating tenofovir-containing HAART and overt renal failure was noted within 5 weeks. Renal biopsy demonstrated histopathologic changes suggestive of HIV nephropathy, despite normal baseline serum creatinine values. Thirty additional cases of tenofovir-associated renal failure have been reported. In the majority (n = 22, 73%), renal failure occurred months after initiating therapy (range: 5-26 months). However, in a significant subset (n = 8, 27%), renal failure occurred within 8 weeks of treatment initiation. Our data suggest that some patients are at risk for developing renal failure within weeks of tenofovir initiation. Thorough evaluation of renal function should be undertaken before prescription of tenofovir-containing HAART. For those in whom subclinical renal disease is discerned, added vigilance when monitoring renal function may be warranted.
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PMID:Early onset of tenofovir-induced renal failure: case report and review of the literature. 1766 Aug 85

The transcription factor peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in lipid homeostasis. In this study, we examined whether the down-regulation of PPAR-alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure (CRF). Rats with laboratory-induced uremia by 5/6 nephrectomy were bled at 2 weeks and 10 weeks after the nephrectomy to produce conditions. For the sake of convenience, the rats observed at postoperative week 2 were defined as acute renal failure (ARF) and those observed at week 10 were defined as CRF. Lipids in lipoprotein fractions were measured by high-performance liquid chromatography. The abundance of PPAR-alpha messenger RNA (mRNA) in the liver was measured by reverse transcriptase-polymerase chain reaction. Serum creatinine and blood urea nitrogen levels rose with the progression of renal failure, but the total protein levels remained constant. Serum triglyceride in ARF rats remained unchanged from the level in sham-operated control rats, whereas that in CRF rats was 66% higher than the control level. Serum cholesterol was elevated 1.5-fold in ARF rats and 2-fold in CRF rats compared with the sham-operated counterparts. As with triglyceride, very low-density lipoprotein remained unchanged in ARF rats but rose substantially in CRF rats. All of the major lipoprotein fractions were elevated in CRF rats. These lipid and lipoprotein changes were significantly associated with creatinine and blood urea nitrogen levels. The PPAR-alpha mRNA expression in the liver was unchanged in ARF rats but was 44% lower in CRF rats. The PPAR-alpha mRNA expression was inversely correlated with serum creatinine and lipids in the overall rats. Our results indicate that PPAR-alpha mRNA expression is down-regulated in the liver of CRF rats and that this down-regulation may play a crucial role in the development of dyslipidemia.
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PMID:Decreased peroxisome proliferator-activated receptor alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure. 1799 26


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