Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced glycation end products (AGEs) are believed to play an important role in the development of angiopathy in diabetes mellitus. Previous reports suggested a correlation between accumulation of AGEs and production of vascular endothelial growth factor (VEGF) in human diabetic retina. However, the mechanisms involved were not revealed. In this study, we investigated the transcriptional regulation of the expression of vascular endothelial growth factor (VEGF) by AGEs, and possible involvement of reactive oxygen species (ROS) in the induction. We employed an AGE of bovine serum albumin (BSA) prepared by an incubation of BSA with D-glucose for 40 weeks and N(epsilon)-(carboxymethyl)lysine (CML), a major AGE. The expression of VEGF was induced by CML-BSA in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the DNA-binding activity of activator protein-1 (AP-1). Promoter assay showed that the induction of VEGF was dependent on AP-1. The activity of Ras/Raf-1/MEK/ERK1/2 was involved in the CML-BSA-stimulated signaling pathways to activate the AP-1 transcription with a peak at 1 h. AGE-BSA also induced VEGF mediated by AP-1, however, there was a difference of effect between AGE-BSA and CML-BSA in the activation of AP-1. AGE-BSA-stimulated AP-1 activity showed a peak at 5 h, which paralleled the formation of ROS. Reduction of AGE-BSA with NaBH(4) or addition of vitamin E attenuated the AGE-BSA-stimulated signaling pathways leading to the same pattern as for CML-BSA-stimulated signals. These results suggest an important role for AGEs in stimulation of the development of angiogenesis observed in diabetic complications, and that ROS accelerates the AGE-stimulated VEGF expression.
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PMID:Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages. 1193 95

The prevalance of hyperlipidemia in chronic renal failure (CRF) patients is higher than in general population. Secondary amyloidosis is a common cause of CRF in Turkey. In this study, 25 patients with CRF due to secondary renal amyloidosis (amyloid-CRF), 15 patients with CRF without amyloidosis-CRF and 17 healthy controls were studied for serum lipid parameters. The mean serum lipoprotein (a) [LP(a)] level in the patients with amyloid-CRF was significantly higher than in the controls (p < 0.01). The mean serum apolipoprotein B (Apo B), apolipoprotein E (Apo E) and triglyceride levels in the patients with amyloid-CRF were very significantly higher than in the controls (p < 0.001). The mean serum total cholesterol, low-density lipoprotein (LDL) levels in the patients with amyloid-CRF were higher than in the controls (p < 0.05). The mean serum apo AI levels in the patients with amyloid-CRF was very significantly lower than in the controls (p < 0.001). The mean serum high-density lipoprotein (HDL) in the patients with amyloid-CRF was lower than in the controls (p < 0.05). The mean serum Lp (a), Apo AI, Apo B and Apo E levels in the patients with amyloid-CRF were significantly higher than in the patients with CRF (p < 0.01). The mean serum total cholesterol, trigliserides, LDL and HDL levels in the patients with amyloid-CRF were higher than in the patients with CRF (p < 0.05). There was not any correlation with serum lipid parameters and serum albumin and urine protein levels (p > 0.05). Our study suggests that serum lipid parameters are abnormal and might be the risk factor of atherosclerotic vascular disease and contribute to renal disease progression in the patients with secondary renal amyloidosis and lipid abnormalities were different from CRF with various etiology, without amyloidosis.
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PMID:Lipoprotein abnormalities in patients with secondary renal amyloidosis. 1198 51

Advanced glycation end products (AGEs) play an important role in the development of angiopathy in diabetes mellitus and atherosclerosis. Here, we show that adducts of N(epsilon)-(carboxymethyl)lysine (CML), a major AGE, and bovine serum albumin (CML-BSA) stimulated gamma-glutamylcysteine synthetase (gamma-GCS), which is a key enzyme of glutathione (GSH) synthesis, in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the expression of gamma-GCS heavy subunit (h) time- and dose-dependently and concomitantly increased GSH levels. CML-BSA also stimulated DNA-binding activity of activator protein-1 (AP-1) within 3h, but the stimulatory effect decreased in 5h, and nuclear factor-kappaB (NF-kappaB) with a peak activity at 1h and the stimulatory effect diminished in 3h. Studies of luciferase activity of the gamma-GCSh promoter showed that deletion and mutagenesis of the AP-1-site abolished CML-BSA-induced up-regulation, while that of NF-kappaB-site did not affect CML-BSA-induced activity. CML-BSA also stimulated the activity of protein kinase C, Ras/Raf-1, and MEK/ERK1/2. Inhibition of ERK1/2 abolished CML-BSA-stimulated AP-1 DNA-binding activity and gamma-GCSh mRNA expression. Our results suggest that induction of gamma-GCS by CML adducts seems to increase the defense potential of cells against oxidative stress produced during glycation processes.
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PMID:Nepsilon-(Carboxymethyl)lysine induces gamma-glutamylcysteine synthetase in RAW264.7 cells. 1214 23

Hyperhomocysteinemia, a risk factor for vascular disease, is found in children as well as in 80% of adult patients with end-stage renal disease. The aim of this study was to assess the changes in plasma homocysteine concentrations after renal transplantation (RT). Plasma homocysteine, vitamin B(12), and folate concentrations were prospectively measured in six patients at three points, before and post transplantation (6 months, 4 years), and compared with controls using standardized scores (Z score) for each of these parameters. Folic acid supplementation was introduced after the evaluation at 6 months. Patients had elevated median plasma homocysteine Z scores during dialysis (4.12). When assessed at 6 months and 4 years, median plasma homocysteine Z scores were, respectively, 2.35 and 0.29. Median folate Z scores were 1.89 during dialysis, -0.26 at 6 months, and 3.26 at 4 years post RT. Median vitamin B(12) Z score was 2.12 during dialysis, 0.58 at 6 months, and -0.07 at 4 years post RT. Glomerular filtration rate (GFR) improved after RT, with median GFR of 84.5 ml/min per 1.73 m(2) at 6 months. This stabilized to a value of 70.5 ml/min per 1.73 m(2) at 4 years. When comparing values before and after RT at 6 months, changes were observed only for GFR ( P<0.03) and vitamin B(12) ( P<0.05). There were no changes in plasma homocysteine, folate, and serum albumin. At 4 years, a significant decrease in plasma homocysteine was observed ( P<0.05) with increased GFR ( P<0.03). No significant changes were observed in plasma albumin, folate, and vitamin B(12) concentrations. In conclusion, elevated plasma homocysteine in children during dialysis persists after RT despite a significant improvement in renal function. However, normalization was attained when patients were supplemented with folic acid. Further controlled studies are required to evaluate the determinants and treatment of elevated plasma homocysteine in pediatric transplant patients.
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PMID:Plasma homocysteine concentration changes after renal transplantation in children. 1217 66

Lipid abnormalities are important variables in the development of vascular atherosclerotic lesions in ESRD patients while Lp(a) represents an independent risk factor. In order to evaluate lipid changes in HD and CAPD patients, serum cholesterol (TC), HDLc, LDLc, TG, apolipoproteins (AI,AII,B,E), Lp(a), and albumin levels were estimated in 109 ESRD dialyzed patients, 46 in HD and 63 in CAPD (mean duration 50 +/- 40 and 25 +/- 19 months, respectively), and 45 volunteers with high serum levels of C and TG, without renal insufficiency. Both HD and PD group revealed statistically significantly higher levels than controls for TC, TG, LDL-C, Apo-B,-E, while HDL-C levels were significantly lower. Except for the lower serum albumin levels in both dialyzed groups after six months lower ApoAI levels and higher ApoB levels were observed in HD and PD patients respectively. Lp(a) levels remained unchanged in HD group, while a statistically significant increase appeared in PD patients that was negative correlated with the decreased serum albumin levels. These results indicate that renal replacement modalities result in a different effect in lipoprotein metabolism that may play an important role in atherosclerotic vascular disease of dialyzed ESRD patients.
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PMID:Lipoprotein abnormalities in hemodialysis and continuous ambulatory peritoneal dialysis patients. 1238 Sep 8

Malnutrition in end-stage renal disease (ESRD) is characterized by hypoalbuminemia, decreased serum creatinine and prealbumin, and decreased subjective global assessment (SGA) scores. Markers of malnutrition predict mortality and correlate closely with inflammatory markers, including serum cytokines and acute phase proteins. After multiple regression analysis, markers of inflammation become stronger predictors of mortality than nutritional markers, suggesting that malnutrition is a result of inflammation. The etiology of inflammation is variable and includes vascular access infection, bioincompatible dialyzers, back filtration of nonsterile dialysate, periodontal disease, urinary tract infections, and other pyogenic infections. Renal failure also may serve to promote inflammation through protein carbonylation. Differences in care patterns of ESRD patients and genetics may contribute to inflammation as evidenced by lower levels of C-reactive protein (CRP) in Asian populations. Inflammation results in loss of muscle mass and hypoalbuminemia as a consequence of its decreased synthesis and increased catabolism. Vascular disease occurs partly because of changes in lipoprotein structure and function, including oxidation of low-density lipoprotein (LDL) and modification of high-density lipoprotein (HDL) by serum amyloid A (SAA) and loss of apolipoprotein A-I. Leukocyte adhesion is promoted by changes in endothelial structure and function, whereas plasma proteins associated with cardiovascular disease (fibrinogen, lipoprotein[a]; SAA) are increased. Consequences of inflammation in ESRD patients include muscle wasting, erythropoetin resistance, and vascular disease. Whereas improvements in nutrition can increase serum albumin and creatinine levels, identification and removal of the underlying cause of inflammation should be one treatment goal.
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PMID:Inflammation in ESRD: causes and potential consequences. 1267 42

C-reactive protein is the prototype marker of inflammation and has been shown to predict mortality in hemodialysis patients. However, it remains uncertain as to whether a single C-reactive protein level has similar prognostic significance in peritoneal dialysis patients. A single high-sensitivity C-reactive protein (hs-CRP) level was measured in 246 continuous ambulatory peritoneal dialysis patients without active infections at study baseline together with indices of dialysis adequacy, echocardiographic parameters (left ventricular mass index, left ventricular dimensions, and ejection fraction), nutrition markers (serum albumin, dietary intake, and subjective global assessment) and biochemical parameters (hemoglobin, lipids, calcium, and phosphate). The cohort was then followed-up prospectively for a median of 24 mo (range, 2 to 34 mo), and outcomes were studied in relation to these parameters. Fifty-nine patients died (36 from cardiovascular causes) during the follow-up period. The median hs-CRP level was 2.84 mg/L (range, 0.20 to 94.24 mg/L). Patients were stratified into tertiles according to baseline hs-CRP, namely those with hs-CRP < or = 1.26 mg/L, 1.27 to 5.54 mg/L, and > or = 5.55 mg/L. Those with higher hs-CRP were significantly older (P < 0.001), had greater body mass index (P < 0.001), higher prevalence of coronary artery disease (P = 0.003), and greater left ventricular mass index (P < 0.001). One-year overall mortality was 3.9% (lower) versus 8.8% (middle) versus 21.3% (upper tertile) (P < 0.0001). Cardiovascular death rate was 2.7% (lower) versus 5.2% (middle) versus 16.2% (upper tertile) (P < 0.0001). Multivariable Cox regression analysis showed that every 1 mg/L increase in hs-CRP was independently predictive of higher all-cause mortality (hazard ratio [HR], 1.02; 95% CI, 1.01 to 1.04; P = 0.002) and cardiovascular mortality (HR, 1.03; 95% CI, 1.01 to 1.05; P = 0.001) in peritoneal dialysis patients. Other significant predictors for all-cause mortality included age (HR, 1.07; 95% CI, 1.04 to 1.10), gender (HR, 0.49; 95% CI, 0.27 to 0.90), atherosclerotic vascular disease (HR, 2.65; 95% CI, 1.46 to 4.80), left ventricular mass index (HR, 1.01; 95% CI, 1.00 to 1.01) and residual GFR (HR, 0.53; 95% CI, 0.38 to 0.75). Age (HR, 1.06; 95% CI, 1.02 to 1.10), history of heart failure (HR, 3.31; 95% CI, 1.36 to 8.08), atherosclerotic vascular disease (HR, 3.20; 95% CI, 1.43 to 7.13), and residual GFR (HR, 0.57; 95% CI, 0.38 to 0.86) were also independently predictive of cardiovascular mortality. In conclusion, a single, random hs-CRP level has significant and independent prognostic value in PD patients.
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PMID:Is a single time point C-reactive protein predictive of outcome in peritoneal dialysis patients? 1281 48

The annual statistical survey conducted at the end of 2000 by the Japanese Society for Dialysis Therapy collected responses from 3358 (99.94%) of 3360 institutions. Japan's total dialysis patient population at the end of the year 2000, as identified by this survey, was 206,134, an increase of 8921 (4.5%) over 1999. This translates to 1624.1 patients per million population. The annual crude mortality rate was 9.4% for the period starting at the end of the year 1999 and ending at the end of the year 2000. The mean patient age at the initiation of dialysis treatment was 63.8 (+/- 13.9; +/- SD) years; the mean age of the overall dialysis patient population was 61.2 years (+/- 13.3). Both these mean ages, which had been increasing since 1983, again continued to increase. Among the primary diagnosis, the prevalence of diabetic nephropathy had continued to increase again since 1999, to 36.6%, whereas that of chronic glomerulonephritis had continued to decline, down to 32.5%, during the same one-year period since the 1999 survey. The 2000 years-end survey incorporated the following additional variables for the first time: usage of oral antihypertensives, pre- and post-dialysis systolic and diastolic blood pressures, serum HDL cholesterol level, types and dosage of oral Vitamin D analogs administered, dosage of oral calcium carbonate administered, history of intervention for peripheral vascular disease (bypass surgery, synthetic graft replacement, stenting), history of coronary artery bypass grafting (CABG), history of percutaneous transluminal coronary angioplasty (PTCA), whether stenting had been previously performed for the treatment of ischemic heart disease, number of cigarettes smoked, the type of vascular access used at the initiation of dialysis, and the year and month the vascular access was created. The survey results indicate that 60.9% of the total dialysis patient population was using oral antihypertensives. The patients' mean serum HDL cholesterol level was 47.65 +/- 18.47 mg/dL, showing positive correlation with serum albumin level and reverse correlation with body mass index. 1.6% of all dialysis patients had previously undergone amputation, and 0.7% had a history of bypass surgery for peripheral vascular disorder. 4.5% of hemodialysis patients had a history of cardiac infarction, 1.6% had previously undergone CABG, and 2.8%, PTCA. At the time the survey was conducted, 2.0% of all dialysis patients were undergoing oral Vitamin D analog pulse therapy, and 6% were undergoing intravenous Vitamin D analog pulse therapy. A history of amputation, myocardial infarction, cerebral infarction, and cerebral bleeding were identified as high-risk factors of vital prognosis. Additionally, high mortality risk was associated with the following: glutamic-pyruvic transaminase levels exceeding 20 IU/L; positive HCV antibody status; comorbid conditions such as hepatic cell carcinoma and liver cirrhosis; platelet counts below 100,000/mL or equal to or greater than 200,000/mL; C-reactive protein levels of 0.2 mg/dL and higher, leukocyte counts of less than 3000/mL or equal to or greater than 8000/mL; and body mass index of below 22 kg/m2, as well as total serum cholesterol levels of below 160 mg/dL or equal to or greater than 260 mg/dL.
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PMID:The current state of chronic dialysis treatment in Japan (as of December 31, 2000). 1292 Nov 11

An elevated calcium x phosphate product (Ca x P) is an independent risk factor for vascular calcification and cardiovascular death in dialysis patients. More physiological dialysis in patients undergoing nocturnal hemodialysis (NHD) has been shown to produce biochemical advantages compared with conventional hemodialysis (CHD) including superior phosphate (P) control. Benefits of dialysate with greater calcium (Ca) concentration are also reported in NHD to prevent Ca depletion and subsequent hyperparathyroidism, but there are concerns that a higher dialysate Ca concentration may contribute to raised serum Ca levels and greater Ca x P and vascular disease. The NHD program at our unit has been established for 4 years, and we retrospectively analyzed Ca and P metabolism in patients undergoing NHD (8-9 h/night, 6 nights/week). Our cohort consists of 11 patients, mean age 49.3 years, who had been on NHD for a minimum of 12 months, mean 34.3 months. Commencement was with low-flux (LF) NHD and 1.5 mmol/L Ca dialysate concentration, with conversion to high-flux (HF) dialyzers after a period (mean duration 18.7 months). We compared predialysis serum albumin, intact parathyroid hormone, P, total corrected Ca, and Ca x P at baseline on CHD, after conversion to LF NHD and during HF NHD. We also prospectively measured bone mineral density (BMD) on all patients entering the NHD program. Bone densitometry (DEXA) scans were performed at baseline (on CHD) and yearly after commencement of NHD. With the introduction of HF dialyzers, the Ca dialysate concentration was concurrently raised to 1.75 mmol/L after demonstration on DEXA scans of worsening osteopenia. Analysis of BMD, for all parameters, revealed a decrease over the first 12 to 24 months (N = 11). When the dialysate Ca bath was increased, the median T and Z scores subsequently increased (data at 3 years, N = 6). The mean predialysis P levels were significantly lower on LF NHD vs. CHD (1.51 vs. 1.77 mmol/L, p = 0.014), while on HF NHD P was lower again (1.33 mmol/L, p = 0.001 vs. CHD). Predialysis Ca levels decreased with conversion from CHD to LF NHD (2.58 vs. 2.47 mmol/L, p = 0.018) using a 1.5 mmol/L dialysate Ca concentration. The mean Ca x P on CHD was 4.56 compared with a significant reduction of 3.74 on LF NHD (p = 0.006) and 3.28 on HF NHD (p = 0.001 vs. CHD), despite the higher dialysate Ca in the latter. We conclude that an elevated dialysate Ca concentration is required to prevent osteopenia. With concerns that prolonged higher Ca levels contribute to increased cardiovascular mortality, the optimal Ca dialysate bath is still unknown. Better P control on NHD, however, reduces the overall Ca x P, despite the increased Ca concentration, therefore reducing the risk of vascular calcification.
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PMID:Calcium phosphate metabolism and bone mineral density with nocturnal hemodialysis. 1680 90

Increased vascular disease occurs with low albumin (human serum albumin, HSA), possibly reflecting specific inhibition of endothelial apoptosis reported for tissue culture. Despite the reported specificity for endothelial protection by HSA, the high but physiological concentrations needed appear more consistent with non-specific low-affinity interactions. We reconcile this contradiction by demonstrating protection is mediated by a partially cryptic HSA protein domain, which becomes more exposed and active following cyanogen bromide fragmentation (p < 0.001). Also, although others reported HSA radical scavenging and bound lipids as important for inhibiting apoptosis in non-endothelial cell types, we demonstrate the protective effect for endothelium is unaffected when HSA radical scavenging is blocked by alkylation, or following delipidation. Further probing the mechanism responsible, we found that the G-coupled protein inhibitors pertussis toxin and suramin reduced protection of endothelium by HSA (p < 0.005), while the tyrosine kinase inhibitor genistein had no effect. Consistent with a role for phosphoinositide 3 kinase (PI3K) was inhibition by both wortmannin and LY294002 (p < 0.05), as well as phosphorylation of Akt, while MAP kinase inhibitors had no effect. We conclude the active site in HSA inhibiting endothelial apoptosis is partially cryptic, and acts via a G-coupled protein PI3K-dependent mechanism.
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PMID:The anti-apoptotic activity of albumin for endothelium is mediated by a partially cryptic protein domain and reduced by inhibitors of G-coupled protein and PI-3 kinase, but is independent of radical scavenging or bound lipid. 1743 60


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