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)

A reciprocal regulation between the expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, demonstrated in monocytes and mesangial cells, provides a rationale for new therapeutic approaches in glomerulonephritis (GN). Administration of IL-10 to mice with antibody-mediated GN attenuated the severity of glomerular lesions. Recently, however, it has been shown that the genetically determined predominance of Th1 or Th2 cytokines results in different glomerular responses to the same planted antigen, but in an equally severe impairment of renal function. We looked for the expression of IL-10 and TNF-alpha in 111 renal biopsy specimens with proliferative and nonproliferative forms of GN and in 10 control kidneys, by means of immunocytochemistry, in situ hybridization, or reverse-transcriptase polymerase chain reaction (RT-PCR). Six patients had acute endocapillary GN (AGN), 10 patients had pauci-immune GN due to microscopic polyangiitis (MP), 48 patients had immunoglobulin-A (IgA)-GN, 18 patients had idiopathic membranous GN (IMGN), 12 patients had minimal change disease (MCD), and 13 patients had focal segmental glomerulosclerosis (FSGS) and four other forms of GN. Antibodies against monocytes (CD14) and macrophages (CD68) were applied to attribute the expression of TNF-alpha and IL-10 to resident renal or infiltrating cells. We show that mRNAs for TNF-alpha and IL-10 are detected by RT-PCR and in situ hybridization in the normal kidney. A constitutive expression of TNF-alpha protein is observed in mesangial cells, smooth muscle cells in renal arteries, and in the interstitium. A trace immunoreactivity for IL-10 is restricted to arterial smooth muscle cells, distal tubular epithelial cells, and some interstitial cells. Upregulation of both cytokines is found in glomerular diseases. The expression of TNF-alpha increases in mesangial areas in MCD, IMGN stages I/II, and IgA-GN with minor glomerular abnormalities, that is, under conditions with a generally well-preserved glomerular structure. Conversely, marked glomerular proliferation in IgA-GN and, particularly, acute vascular lesions in MP, are accompanied by a significant upregulation of IL-10 (at the mRNA and protein level). Patients with nephrotic-range proteinuria show a significant increase in tubulointerstitial expression of IL-10, whereas the immunoreactivity for TNF-alpha reflects the extent of interstitial fibrosis. Thus, our results confirm previous suggestions that proinflammatory and antiinflammatory cytokines are produced in situ by resident renal cells and contribute to the natural course of human GN.
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PMID:In situ upregulation of IL-10 reflects the activity of human glomerulonephritides. 966 28

Numerous renal abnormalities accompany thyroid disease, most of which have been ascribed to the effects of thyroid hormone on renal metabolism. In the present report, we investigate the renal expression of the nominally thyroid-specific proteins, thyroid-stimulating hormone (TSH) receptor (TSHR) and thyroglobulin (Tg), as potential links between renal and thyroid function. The expression of TSHR has been identified in several extrathyroidal tissues, but its presence in the kidney remains controversial. We have used reverse-transcriptase polymerase chain reaction and DNA sequencing to demonstrate the presence of TSHR transcript in human and mouse kidney, in a primary culture of human kidney, and in a green monkey kidney epithelioid cell line. Furthermore, human kidney cells responded to TSH with a 2.5- fold increase in intracellular cyclic adenosine monophosphate, suggesting the presence of functional TSHR protein. Comparison of renal expression of TSHR in a bovine growth hormone transgenic mouse model of progressive glomerulosclerosis with control mice suggested increased TSHR transcript in the renal cortex of transgenic animals. TSHR transcript was also detected in mouse mesangial cells in vitro which responded to TSH with significant increases in the formation of three-dimensional hillhocks. Polymerase chain reaction also confirmed the presence of Tg transcript in human and mouse kidneys and in mouse mesangial cells, but no effect of either TSH or cyclic adenosine monophosphate on Tg transcript levels could be discerned. Immunofluorescent staining with a monoclonal anti-Tg antibody identified positive staining in the cytoplasm of mesangial cells. These data suggest that the kidney is capable of expressing the thyroid-specific genes, TSHR and Tg, which could conceivably mediate effects of thyroid disease in the kidney.
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PMID:Renal expression of two 'thyroid-specific' genes: thyrotropin receptor and thyroglobulin. 1094 Jul 22

Endothelin (ET) receptor antagonists are nephroprotective in renal damage models of the rat. It is unknown whether ET receptor antagonists are also beneficial in human renal diseases. Major differences exist between the ET systems in rats and humans, therefore this study was designed to characterize the ET receptors expressed on human adult mesangial cells (HMCs). HMCs cultures are a surrogate model for the development of glomerulosclerosis. Binding experiments with [125I]ET-1 in the presence or the absence of the test compounds [endothelin-1, -3 (ET-1, ET-3), sarafotoxin 6c (S6c), or BQ123] revealed an affinity (IC50 values) of 10.5 nm for ET-1 and 87.6 nm for ET-3. The affinities of the ET(B) agonist S6c and the ET(A) antagonist BQ123 were 85.9 nm and > 10 microm, respectively. Thus, the ET receptor on HMCs shows an ET(B)-like pharmacology, but in contrast to the classical ET(B)-receptor the affinities are low. No affinity for BQ123 up to > 10 microm excludes the presence of ET(A)-receptors. Functional studies using microfluorimetry (fura-2 method) showed comparable biphasic calcium signals induced by 10 nm ET-1, ET-3 and S6c. This effect could not be inhibited by BQ123, but by the ET(B) antagonist BQ788. Reverse transcriptase polymerase chain reaction (RT-PCR) studies under different culture conditions showed that both ET(A)- and ET(B)-receptor mRNAs are expressed in HMCs. The amount of ET(A)-receptor mRNA increased 2.7-fold and that of the ET(B)-receptor mRNA 7.1-fold after stimulation with 10% fetal calf serum (FCS). ET-1, ET-3 and S6c stimulated HMCs growth (ET-1 > S6c > ET-3), but the magnitude of the effect of ET-1 is lower than reported in rat mesangial cells (rat MCs). The effect on HMCs growth could be inhibited by BQ788, but not by BQ123. Our data provide evidence for the expression of ET(B)-receptors on HMCs that are functionally active. This finding differs from the ET receptor expression in rat MCs as reported by others.
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PMID:Adult human mesangial cells (HMCs) express endothelin-B-receptors which mediate endothelin-1-induced cell growth. 1107 85

Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4 degrees C for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d, respectively (P < 0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P < 0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P < 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-beta-gal group at all time points. Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased before reperfusion (P < 0.001) and remained increased in the Ad-HO-1-treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-beta-gal controls (P < 0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury.
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PMID:Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury. 1259 12

In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.
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PMID:Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension. 1562 40

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

The tissue kallikrein-kinin system is important in regulating cardiovascular and renal function, and dysregulation of the system has been implicated in heart and kidney pathologies. These findings suggest that if balance can be restored to the kallikrein-kinin axis, then associated disease progression may be attenuated. To test this hypothesis, recombinant adeno-associated virus (rAAV)-mediated human tissue kallikrein (HK) expression was induced in a rodent model of chronic renal failure involving 5/6 nephrectomy (nephrectomy plus 70% reduction of remaining kidney). rAAV-HK treatment attenuated the rise in blood pressure, glomerular sclerosis, and tubulointerstitial injury observed in this model. rAAV-HK treatment also attenuated renal function decline as measured by urinary microalbumin, osmolarity, and cGMP levels. Reverse transcriptase-polymerase chain reaction analysis showed that rAAV-HK-treated rats had higher levels of bradykinin receptor-2 (B(2)R) and dopamine receptor-1 mRNAs. In contrast, angiotensin II receptor-1, endothelin receptor-A, and vasopressin receptor-2 mRNAs were markedly downregulated in kidneys from HK-treated rats. Bradykinin induced similar changes in receptor levels and prevented transforming growth factor-beta(1)-induced tubulointerstitial fibrosis. The effects of bradykinin could be reversed with the B(2)R antagonist HOE-140. Together, these findings suggest that restoration of the kallikrein-kinin system reduces kidney injury and protects renal function in 5/6-nephrectomized rats via changes in the expression and activation of G protein-coupled receptors including B(2)R.
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PMID:Delivery of recombinant adeno-associated virus-mediated human tissue kallikrein for therapy of chronic renal failure in rats. 1840 47