Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mortality rate in hemodialysis patients remains extremely high, and reduced serum albumin concentration resulting from malnutrition is the strongest predictor of mortality and morbidity. Several inflammatory cytokines involved in malnutrition, including interleukin-1, interleukin-6, and tumor necrosis factor-alpha, are modulated by 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], of which synthesis is impaired in end-stage renal disease. We evaluated whether 1,25-(OH)(2)D(3) deficiency might be involved in reduced serum albumin concentrations. Fifty-one predialysis uremic patients about to begin hemodialysis therapy were divided into groups with serum 1,25-(OH)(2)D(3) concentrations less than 18 pg/mL (low-D(3) group; n = 39) and concentrations of 18 pg/mL or greater (normal-D(3) group; n = 12). Serum albumin concentrations before the initiation of hemodialysis treatment were compared between the two groups. Furthermore, the effect of supplementation with active forms of vitamin D during 4 months of hemodialysis treatment on serum albumin concentrations was retrospectively evaluated in the low-D(3) group. Serum albumin concentrations in the low-D(3) group were significantly less than those in the normal-D(3) group (3.58 +/- 0. 50 versus 3.82 +/- 0.10 g/dL; P = 0.034). Considering all patients, a significant positive correlation between serum concentrations of albumin and 1,25-(OH)(2)D(3) was noted (r = 0.417; P = 0.0023). Supplementation with active forms of vitamin D significantly increased serum albumin concentrations in the low-D(3) group from 3. 61 +/- 0.12 to 3.79 +/- 0.13 g/dL (P = 0.0067). These findings indicate that reductions in serum albumin concentrations may be attributed, at least in part, to vitamin D deficiency in patients with end-stage renal disease.
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PMID:Vitamin D deficiency is implicated in reduced serum albumin concentrations in patients with end-stage renal disease. 1092 12

Paricalcitol (19-nor-1,25-dihydroxyvitamin D(2)), a new vitamin D analogue, recently became available for the treatment of hyperparathyroidism in patients with end-stage renal disease. It is safe and effective in suppressing parathyroid hormone, with apparently less propensity for hypercalcemia than calcitriol (1, 25-dihydroxyvitamin D(3)). However, the mechanism of action on bone has not been fully elucidated. This study compares the effects of paricalcitol and calcitriol on the bone mineral. Neonatal (5- to 7-day-old) mouse calvariae were incubated in the absence or presence of either paricalcitol or calcitriol for 48 hours, and calcium flux, osteocalcin and acid and alkaline phosphatase activity, and interleukin-6 (IL-6) release were determined. Increasing concentrations of both calcitriol and paricalcitol increased calcium efflux. At lower concentrations, paricalcitol had no effect on acid phosphatase activity; however, at 10(-8) mol/L, paricalcitol caused a significant increase similar to that of calcitriol at 10(-9) mol/L. Increasing concentrations of paricalcitol had no effect on alkaline phosphatase activity, whereas calcitriol (10(-8) mol/L) caused significant inhibition. At low concentrations, paricalcitol had no effect on osteocalcin release; however, at 10(-8) mol/L, both compounds significantly increased osteocalcin production. Neither compound had an effect on IL-6 release. These data show that: (1) at low concentrations, both compounds induce a similar calcium efflux from cultured bone; (2) at low concentrations, paricalcitol has no effect on osteocalcin or acid and alkaline phosphatase activity; (3) at greater concentrations, paricalcitol and calcitriol have similar effects on acid phosphatase and osteocalcin activity; (4) calcitriol, but not paricalcitol, inhibits alkaline phosphatase release; and (5) the bone-resorbing effect of both compounds is independent of IL-6 release. Thus, although both compounds have similar effects on calcium efflux from bone, at therapeutic concentrations, paricalcitol does not seem to inhibit osteoblast activity. This may explain, in part, the lower calcemic effect of paricalcitol.
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PMID:Effect of the vitamin D analogues paricalcitol and calcitriol on bone mineral in vitro. 1100 82

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-mediated lowering of serum cholesterol has been associated with a significant reduction in cardiovascular morbidity and mortality. Recent studies suggest that additional non-lipid lowering effects (eg, endothelial stabilization, anti-inflammatory, antithrombogenic) may be important in modulating their effectiveness. Dyslipidemia is common in end-stage renal disease (ESRD), and hemodialysis patients have increased cardiovascular morbidity and mortality. Cerivastatin, a new statin with powerful low-density lipoprotein-cholesterol (LDL-C) lowering capabilities, possesses some unique non-LDL-C-mediated properties that may contribute to a reduction of coronary events in the patient with ESRD. The primary objective of this multicenter multinational study of 1,054 hemodialysis patients is to compare 2 years of treatment with cerivastatin (0.4 mg/d) versus placebo on the composite clinical event rate of myocardial infarction, sudden cardiac death, ischemic stroke, and the need for coronary arterial bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) procedures in these patients. Changes in lipids, inflammatory proteins including heat stable C-reactive protein (hsCRP), interleukin-6 (IL-6), oncostatin-M, intracellular adhesion molecule-1 (ICAM-1) and monocyte-chemoattractant protein-1 (MCP-1), as well as markers of cardiac muscle pathology, such as troponin I and troponin T, will be assessed in a subset of patients. This study is the first of its kind to assess the effect of a statin on the reduction of cardiovascular morbidity and mortality in an incident hemodialysis population. It will determine whether treatment with cerivastatin can effectively reduce the significant cardiovascular morbidity and mortality.
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PMID:The CHORUS (Cerivastatin in Heart Outcomes in Renal Disease: Understanding Survival) protocol: a double-blind, placebo-controlled trial in patients with esrd. 1115 61

Few studies have examined the role of the microvasculature in progressive renal disease. It was hypothesized that impaired angiogenesis might occur in the diseased kidney and could contribute to renal scarring. Progressive renal disease was induced in rats by 5/6 renal ablation and those rats were compared with sham-operated control animals at multiple time points, for examination of changes in the microvasculature and the expression of angiogenic factors. An early angiogenic response was documented in remnant kidneys, with increases in the proliferation of peritubular (1 wk) and glomerular (2 wk) endothelial cells. Subsequently, however, there was a decrease in endothelial cell proliferation, which was reduced to levels below those of sham-treated animals, in conjunction with interstitial expression of the antiangiogenic factor thrombospondin-1 (TSP-1) and decreased tubular expression of the proangiogenic factor vascular endothelial growth factor (VEGF). Both the increase in TSP-1 expression and the loss of VEGF expression were correlated with capillary loss and the development of glomerulosclerosis and interstitial fibrosis. Progressive macrophage infiltration was correlated both spatially and quantitatively with the sites of absent or diminished VEGF expression. In addition, macrophage-associated cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) inhibited VEGF mRNA expression and protein secretion by cultured tubular epithelial cells of the medullary thick ascending limb, under both normoxic and hypoxic conditions. Impaired angiogenesis characterizes the remnant kidney model and is correlated with progression. The impaired angiogenesis may be mediated by alterations in the renal expression of TSP-1 and VEGF, with the latter being regulated by macrophage-associated cytokines.
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PMID:Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. 1142 72

Mortality is markedly elevated in patients with end-stage renal disease. The leading cause of death is cardiovascular disease. Lipoprotein levels are only slightly elevated in dialysis patients, and cardiovascular risk is inversely correlated with serum cholesterol, suggesting that a process other than hyperlipidemia plays a role in the incidence of cardiovascular disease. Hypoalbuminemia, ascribed to malnutrition, has been one of the most powerful risk factors that predict all-cause and cardiovascular mortality in dialysis patients. The presence of inflammation, as evidenced by increased levels of specific cytokines (interleukin-6 and tumor necrosis factor alpha) or acute-phase proteins (C-reactive protein and serum amyloid A), however, has been found to be associated with vascular disease in the general population as well as in dialysis patients. The process of inflammation, also called the acute-phase response, additionally causes loss of muscle mass and changes in plasma composition-decreases in serum albumin, prealbumin, and transferrin levels, also associated with malnutrition. Inflammation alters lipoprotein structure and function as well as endothelial structure and function to favor atherogenesis and increases the concentration of atherogenic proteins in serum, such as fibrinogen and lipoprotein (a). Inflammation in dialysis patients is episodic. The causes are likely to be multifactorial and include vascular access infection, less-than-sterile dialysate, dialysate back leak, and nonbiocompatible membranes in addition to clinically apparent infection. In addition, proinflammatory compounds, such as advanced glycation end products, accumulate in renal failure, and defense mechanisms against oxidative injury are reduced, contributing to inflammation and to its effect on the vascular endothelium.
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PMID:The microinflammatory state in uremia: causes and potential consequences. 1142 86

The cardiovascular mortality rate is unacceptably high in patients with end-stage renal disease (ESRD), which suggests an accelerated atherogenic process. The cause(s) of the accelerated atherogenesis in ESRD patients are not known, though recent studies suggest that persistent infection, such as Chlamydia pneumoniae, and proinflammatory cytokines may contribute. Forty-five ESRD patients (26 men) aged 51 +/- 2 years was studied at a time-point close to start of dialysis treatment and again after about 12 months of dialysis treatment. By using noninvasive B-mode ultrasonography, we evaluated changes in a surrogate marker of atherosclerosis, calculated intima media (cIM) area, in the common carotid artery. C-reactive protein (CRP), S-albumin, and interleukin-6 (IL-6) assessed the presence of an inflammatory reaction. We also measured C pneumoniae antibodies by microimmunofluorescence, nutritional status by subjective global assessment, lipid parameters, smoking habits, and the presence of comorbidity close to the start of dialysis. No significant changes in the prevalence of carotid plaques or the mean cIM area were observed during the first 12 months of dialysis. However, because some patients showed marked increases in the cIM area during only 12 months of dialysis we divided the patients into 2 groups: 23 nonprogressors ((delta)cIM area -2.7 +/- 0.4 mm2) and 22 progressors ((delta)cIM area 3.6 +/- 0.7 mm2). Sex, age, body mass index, comorbidity, blood lipid levels, S-albumin, and CRP levels did not differ significantly between the 2 groups. On the other hand, progressors had a significantly elevated basal median level of IL-6 (5.7 versus 3.1 pg/mL; P < 0.05) and an increased prevalence of positive (> or 1/64) immunoglobulin (Ig) A antichlamydia antibodies (59% versus 17%; P < 0.01) compared with nonprogressors. A significant positive (R = 0.41; P < 0.01) correlation was found between Log IL-6 and changes in the cIM area during 12 months of dialysis. In a stepwise multiple regression model, Log IL-6 did predict, independently (P < 0.01) of traditional risk factors and C pneumoniae antibodies, changes in the cIM area. These data suggest that a persistent chlamydial infection stimulates IL-6 levels, which in turn may be involved in the pathogenesis of accelerated carotid atherosclerosis in dialysis patients.
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PMID:Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity. 1184 Mar 67

The reason for the elevation of fibrinogen concentration in diabetic patients with nephropathy is not known so far. In order to elucidate the mechanism of such an increase in fibrinogen levels, we investigated haemorheological and inflammatory markers in type 2 diabetic patients in a cross-sectional design. Thirty-two non-smoking type 2 diabetic patients (13 women, 19 men; body mass index 29.1+/-5.4 kg/m2, age 62.8+/-12.1 years) were investigated. Patients with C-reactive protein levels >1.5 mg/dl were excluded from the study. Concentration of fibrinogen was measured by immunonephelometry, C-reactive protein by immunoturbidimetry, and interleukin-6 (IL-6) by an enzyme-linked immunosorbent assay, and viscosity of plasma and of whole blood was determined by rotation viscosimetry. Concentrations of inflammatory parameters were well correlated with each other (p<0.05 for all correlations): IL-6 with C-reactive protein (r=0.48), and C-reactive protein with fibrinogen (r=0.41). While no associations were found with concentrations of C-reactive protein or IL-6, urinary albumin excretion was correlated with erythrocyte sedimentation rate (r=0.47) and with fibrinogen concentration (r=0.39; p<0.05). In patients with type 2 diabetes mellitus, urinary albumin excretion was not associated with concentrations of IL-6 or C-reactive protein. These results suggest an IL-6-independent mechanism for increased fibrinogen levels and erythrocyte sedimentation rate in type 2 diabetic patients with increased urinary albumin excretion.
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PMID:Lack of an association of urinary albumin excretion with interleukin-6 or C-reactive protein in patients with type 2 diabetes. 1185 92

Until now, hepatocytes have been the only known cell source of macrophage-stimulating protein (MSP), and tissue macrophages have been the cells on which the biologic effects of MSP have been proved. To extend the understanding of the biologic meaning of MSP, it was investigated whether MSP operates in the kidney. MSP protein was evaluated by Western blot in supernatant of cultured human tubular cells (HK2) and human mesangial cells (HMC). MSP mRNA was investigated in HK2 by reverse transcription-polymerase chain reaction (RT-PCR). The expression of the MSP receptor, RON, was evaluated in HMC and HK2 by Western blot. RON mRNA was investigated in HMC by RT-PCR. The expression of MSP and RON in normal human renal tissue was studied by immunohistochemistry. HMC were stimulated with recombinant MSP (rMSP) and HK2 supernatant to study cell growth, migration, and the capacity to invade an artificial collagen matrix and synthesize interleukin-6 (IL-6). HK2 produced MSP and expressed RON in a form that was phosphorylated by rMSP. HMC expressed RON but did not produce MSP. MSP in HK2 supernatant and rMSP induced in HMC phosphorylation of RON, growth, migration, invasion, and IL-6 synthesis. In normal human kidney, tubules expressed MSP and RON. These results indicate a novel field of operation for MSP and suggest a pathogenic role of the MSP/RON system in renal disease. In fact, MSP released by tubular cells may recruit monocytes/macrophages in inflammatory tubulointerstitial disorders. In addition, MSP either circulating or as paracrine product may sustain glomerular mesangioproliferative disease.
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PMID:Macrophage-stimulating protein is produced by tubular cells and activates mesangial cells. 1185 68

In spite of its high impact on cardiovascular and renal disease, knowledge on risk factors for the development of high blood pressure (HBP) is limited. Mild chronic inflammation may play a significant role in the incidence of HBP. A persistent low-grade inflammation state could be associated with high but within the 'normal range' cytokine plasma concentration. By impairing the capacity of the endothelium to generate vasodilating factors, particularly nitric oxide (NO), elevated cytokines may lead to the development of endothelial dysfunction, chronic impaired vasodilation, and HBP. These alterations in the L-arginine : NO pathway may play a major role in the development of HBP in young subjects, with inflammation-related alterations in the production of cyclo-oxygenase-derived vasoconstrictors becoming more prominent with advanced age. Cross-sectional independent associations between HBP and plasma levels of C-reactive protein, interleukin-6, and tissue necrosis factor alpha have been reported, but no prospective evidence of these associations is currently available.
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PMID:Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence. 1269 66

Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD) patients and there is emerging evidence that genetic factors may contribute to the development of atherosclerosis. Myeloperoxidase (MPO) is an abundant enzyme involved in the production of free radicals. A functional G-->A single nucleotide polymorphism (SNP) has been identified at position -463, where the A allele is associated with lower MPO expression. To analyze the association between this SNP and inflammation, oxidative stress, and CVD, we studied a cohort of 155 ESRD patients (52 +/- 1 years, 62% males, 22% diabetics) shortly before the initiation of dialysis treatment. CVD was defined by medical history criteria; plasma interleukin-6 (IL-6) was used as a marker of inflammation, and plasma pentosidine as an estimation of oxidative protein damage. DNA from leukocytes was used for genotyping, performed by the pyrosequencing reaction. Only five patients (3%) had the genotype AA at the -463 position, whereas 38 (25%) had the GA and 112 (72%) had the GG genotype. No differences were noted in plasma IL-6 levels between the genotype groups, whereas the pentosidine levels were higher in the GG group (28.4 pmol/mg albumin [range, 8.5 to 123 pmol/mg albumin]) compared to the other two groups (21.4 pmol/mg albumin [range, 7.6 to 384 pmol/mg albumin; P < 0.05]). Patients with the GG genotype had a higher prevalence of positive serology for Chlamydia pneumoniae (51%) when compared to the carriers of the A allele (24%) (P < 0.05). The prevalence of CVD was lower in the AA (0%) and GA genotypes (18%), compared to the GG genotype (35%). The GG genotype was still associated with CVD after correction for age, diabetes, smoking, malnutrition, and inflammation. Our findings suggest that the -463 G-->A SNP, which supposedly results in lower MPO activity, is associated with a lower prevalence of CVD in ESRD patients. It could be speculated that this effect is mediated by a decreased oxidative stress due to lower production of free radicals.
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PMID:A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. 1284 78


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