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1.
Article in English | WPRIM | ID: wpr-762455

ABSTRACT

BACKGROUND: Anti-carbohydrate antibody responses, including those of anti-blood group ABO antibodies, are yet to be thoroughly studied in humans. Because anti-ABO antibody-mediated rejection is a key hurdle in ABO-incompatible transplantation, it is important to understand the cellular mechanism of anti-ABO responses. We aimed to identify the main human B cell subsets that produce anti-ABO antibodies by analyzing the correlation between B cell subsets and anti-ABO antibody titers. METHODS: Blood group A-binding B cells were analyzed in peritoneal fluid and peripheral blood samples from 43 patients undergoing peritoneal dialysis and 18 healthy volunteers with blood group B or O. The correlation between each blood group A-specific B cell subset and anti-A antibody titer was then analyzed using Pearson's correlation analysis. RESULTS: Blood group A-binding B cells were enriched in CD27⁺CD43⁺CD1c− B1, CD5⁺ B1, CD11b⁺ B1, and CD27⁺CD43⁺CD1c+ marginal zone-B1 cells in peripheral blood. Blood group A-specific B1 cells (P=0.029 and R=0.356 for IgM; P=0.049 and R=0.325 for IgG) and marginal zone-B1 cells (P=0.011 and R=0.410 for IgM) were positively correlated with anti-A antibody titer. Further analysis of peritoneal B cells confirmed B1 cell enrichment in the peritoneal cavity but showed no difference in blood group A-specific B1 cell enrichment between the peritoneal cavity and peripheral blood. CONCLUSIONS: Human B1 cells are the key blood group A-specific B cells that have a moderate correlation with anti-A antibody titer and therefore constitute a potential therapeutic target for successful ABO-incompatible transplantation.


Subject(s)
Antibodies , Antibody Formation , Ascitic Fluid , B-Lymphocyte Subsets , B-Lymphocytes , Healthy Volunteers , Humans , Immunoglobulin M , Peritoneal Cavity , Peritoneal Dialysis
2.
Experimental Neurobiology ; : 404-413, 2019.
Article in English | WPRIM | ID: wpr-763765

ABSTRACT

Cognitive impairments and motor dysfunction are commonly observed behavioral phenotypes in genetic animal models of neurodegenerative diseases. JNPL3 transgenic mice expressing human P301L-mutant tau display motor disturbances with age- and gene dose-dependent development of neurofibrillary tangles, suggesting that tau pathology causes neurodegeneration associated with motor behavioral abnormalities. Although gait ignition failure (GIF), a syndrome marked by difficulty in initiating locomotion, has been described in patients with certain forms of tauopathies, transgenic mouse models mirroring human GIF syndrome have yet to be reported. Using the open field and balance beam tests, here we discovered that JNPL3 homozygous mice exhibit a marked delay of movement initiation. The elevated plus maze excluded the possibility that hesitation to start in JNPL3 mice was caused by enhanced levels of anxiety. Considering the normal gait ignition in rTg4510 mice expressing the same mutant tau in the forebrain, GIF in JNPL3 mice seems to arise from abnormal tau deposition in the hindbrain areas involved in locomotor initiation. Accordingly, immunohistochemistry revealed highly phosphorylated paired helical filament tau in JNPL3 brainstem areas associated with gait initiation. Together, these findings demonstrate a novel behavioral phenotype of impaired gait initiation in JNPL3 mice and underscore the value of this mouse line as a tool to study the neural mechanisms and potential treatments for human GIF syndrome.


Subject(s)
Animals , Anxiety , Brain Stem , Cognition Disorders , Gait , Humans , Immunohistochemistry , Locomotion , Mice , Mice, Transgenic , Models, Animal , Neurodegenerative Diseases , Neurofibrillary Tangles , Pathology , Phenotype , Prosencephalon , Rhombencephalon , Tauopathies
3.
Article in English | WPRIM | ID: wpr-786196

ABSTRACT

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare but near-fatal complication of peritoneal dialysis (PD). Despite the high mortality rate of EPS, the surgical treatment strategy of severe EPS is yet to be established.METHODS: We retrospectively analyzed outcomes of patients with EPS who underwent enterolysis for intractable EPS at Seoul National University Hospital between 2001 and 2018. EPS was diagnosed based on the clinical symptoms and radiological findings of abdominal computed tomography (CT). CT scans were scored according to an EPS scoring system that assessed peritoneal thickening and calcification as well as bowel thickening, tethering, loculation, and dilatation.RESULTS: Thirteen patients (nine males and four females; age, 48 [29–63] years) underwent enterolysis for severe EPS. PD duration (11 [6–21] years) was not associated with survival. Two patients were newly diagnosed with EPS following kidney transplantation. Five patients died of infectious complications immediately after the surgery. Eight patients survived after the first surgery; however, five of them underwent reoperation but died of persistent infection, fistula formation, or adhesive bowel obstruction. Four young (< 60 years) male patients with relatively low CT scan scores (< 13) survived for > 2 years after the first surgery. Median survival duration from EPS diagnosis was 22 (1.3–184) months and that from the first surgery was 9 (0.3–153) months.CONCLUSION: The high mortality rate of EPS suggests the importance of appropriate surgical intervention in young symptomatic male EPS patients with relatively low CT scan scores.


Subject(s)
Adhesives , Diagnosis , Dilatation , Female , Fistula , Humans , Kidney Transplantation , Korea , Male , Mortality , Peritoneal Dialysis , Peritoneal Fibrosis , Reoperation , Retrospective Studies , Seoul , Tomography, X-Ray Computed
4.
Article in English | WPRIM | ID: wpr-186621

ABSTRACT

PURPOSE: Neointimal hyperplasia (NH) is considered to be one of the main causes of vascular access occlusion in patients receiving hemodialysis. Endothelial injury and TGF-β-mediated proliferation of vascular smooth muscle cells (VSMCs) induce NH. Endothelial microparticles (EMPs) are also increased by endothelial injury. We aimed to investigate the effects of EMPs and TGF-β expression on VSMC proliferation and their contributions to NH formation in an ex vivo model. METHODS: EMPs were collected from the culture media of human umbilical vein endothelial cells treated with indoxyl sulfate (IS, 250 µg/mL) after ultracentrifugation at 100,000 × g. Porcine internal jugular veins were isolated and treated with EMPs (2 × 10⁶ /mL) or left untreated for 12 days and subsequently compared with TGF-β (10 ng/mL)-treated venous tissue. Intima-media thickness and NH area were assessed using a digital program. Masson's trichrome staining and immunohistochemistry (IHC) analysis for α-smooth muscle actin, phosphorylated Akt, ERK1/2, p38 mitogen-activated protein kinase (MAPK), and Smad3 were performed on each vein sample. RESULTS: NH and VSMC proliferation developed to a significantly greater degree in EMP-treated veins compared to controls, with similar patterns seen in TGF-β-stimulated samples. IHC analysis demonstrated that EMPs markedly increased phosphorylation of Akt, ERK1/2, p38 MAPK, and Smad3 in areas of venous NH formation. CONCLUSION: Our results showed that IS-induced EMPs provoked massive VSMC proliferation and NH formation via activation of the TGF-β signaling pathways. Further investigation is needed to elucidate the precise mechanism of EMP activity on vascular access stenosis in vivo.

5.
Yonsei Medical Journal ; : 942-949, 2016.
Article in English | WPRIM | ID: wpr-63328

ABSTRACT

PURPOSE: Endothelial dysfunction (ED) is a pivotal phenomenon in the development of cardiovascular disease (CVD) in patients receiving hemodialysis (HD). Indoxyl sulfate (IS) is a known uremic toxin that induces ED in patients with chronic kidney disease. The aim of this study was to investigate whether AST-120, an absorbent of IS, improves microvascular or macrovascular ED in HD patients. MATERIALS AND METHODS: We conducted a prospective, case-controlled trial. Fourteen patients each were enrolled in respective AST-120 and control groups. The subjects in the AST-120 group were treated with AST-120 (6 g/day) for 6 months. Microvascular function was assessed by laser Doppler flowmetry using iontophoresis of acetylcholine (Ach) and sodium nitroprusside (SNP) at baseline and again at 3 and 6 months. Carotid arterial intima-media thickness (cIMT) and flow-mediated vasodilation were measured at baseline and 6 months. The Wilcoxon rank test was used to compare values before and after AST-120 treatment. RESULTS: Ach-induced iontophoresis (endothelium-dependent response) was dramatically ameliorated at 3 months and 6 months in the AST-120 group. SNP-induced response showed delayed improvement only at 6 months in the AST-120 group. The IS level was decreased at 3 months in the AST-120 group, but remained stable thereafter. cIMT was significantly reduced after AST-120 treatment. No significant complications in patients taking AST-120 were reported. CONCLUSION: AST-120 ameliorated microvascular ED and cIMT in HD patients. A randomized study including a larger population will be required to establish a definitive role of AST-120 as a preventive medication for CVD in HD patients.


Subject(s)
Acetylcholine , Adult , Carbon/therapeutic use , Cardiovascular Diseases/etiology , Carotid Intima-Media Thickness , Endothelium, Vascular/physiopathology , Female , Humans , Iontophoresis , Kidney Failure, Chronic/complications , Laser-Doppler Flowmetry , Male , Microcirculation/physiology , Middle Aged , Nitroprusside , Oxides/therapeutic use , Prospective Studies , Renal Dialysis , Young Adult
6.
Yonsei Medical Journal ; : 1446-1453, 2016.
Article in English | WPRIM | ID: wpr-143175

ABSTRACT

PURPOSE: Chronic kidney disease (CKD) patients tend to have higher serum magnesium values than healthy population due to their positive balance of magnesium in kidney. Recent studies found that magnesium level is positively correlated with endothelial function. Therefore, this study was conducted to define the relationship between magnesium level and endothelial dysfunction in end stage renal disease (ESRD) patients on hemodialysis (HD). MATERIALS AND METHODS: A total of 27 patients were included in this cross-sectional study. Iontophoresis with laser-Doppler flowmetry, flow mediated dilation (FMD), and carotid intima-media thickness were measured. Patients' average serum magnesium levels were measured over previous three months, including the examination month. Pearson's correlation coefficient analysis and multivariate regression model were used to define the association between magnesium and endothelial function. RESULTS: In the univariate analysis, higher magnesium levels were associated with better endothelium-dependent vasodilation (EDV) of the FMD in ESRD patients on HD (r=0.516, p=0.007). When the participants were divided into two groups according to the median magnesium level (3.47 mg/dL), there was a significant difference in EDV of FMD (less than 3.47 mg/dL, 2.8±1.7%; more than 3.47 mg/dL, 5.1±2.0%, p=0.004). In multivariate analysis, magnesium and albumin were identified as independent factors for FMD (β=1.794, p=0.030 for serum magnesium; β=3.642, p=0.012 for albumin). CONCLUSION: This study demonstrated that higher serum magnesium level may be associated with better endothelial function in ESRD patients on HD. In the future, a large, prospective study is needed to elucidate optimal range of serum magnesium levels in ESRD on HD patients.


Subject(s)
Carotid Intima-Media Thickness , Cross-Sectional Studies , Endothelium , Humans , Iontophoresis , Kidney , Kidney Failure, Chronic , Laser-Doppler Flowmetry , Magnesium , Microcirculation , Multivariate Analysis , Prospective Studies , Renal Dialysis , Renal Insufficiency, Chronic , Vasodilation
7.
Yonsei Medical Journal ; : 1446-1453, 2016.
Article in English | WPRIM | ID: wpr-143170

ABSTRACT

PURPOSE: Chronic kidney disease (CKD) patients tend to have higher serum magnesium values than healthy population due to their positive balance of magnesium in kidney. Recent studies found that magnesium level is positively correlated with endothelial function. Therefore, this study was conducted to define the relationship between magnesium level and endothelial dysfunction in end stage renal disease (ESRD) patients on hemodialysis (HD). MATERIALS AND METHODS: A total of 27 patients were included in this cross-sectional study. Iontophoresis with laser-Doppler flowmetry, flow mediated dilation (FMD), and carotid intima-media thickness were measured. Patients' average serum magnesium levels were measured over previous three months, including the examination month. Pearson's correlation coefficient analysis and multivariate regression model were used to define the association between magnesium and endothelial function. RESULTS: In the univariate analysis, higher magnesium levels were associated with better endothelium-dependent vasodilation (EDV) of the FMD in ESRD patients on HD (r=0.516, p=0.007). When the participants were divided into two groups according to the median magnesium level (3.47 mg/dL), there was a significant difference in EDV of FMD (less than 3.47 mg/dL, 2.8±1.7%; more than 3.47 mg/dL, 5.1±2.0%, p=0.004). In multivariate analysis, magnesium and albumin were identified as independent factors for FMD (β=1.794, p=0.030 for serum magnesium; β=3.642, p=0.012 for albumin). CONCLUSION: This study demonstrated that higher serum magnesium level may be associated with better endothelial function in ESRD patients on HD. In the future, a large, prospective study is needed to elucidate optimal range of serum magnesium levels in ESRD on HD patients.


Subject(s)
Carotid Intima-Media Thickness , Cross-Sectional Studies , Endothelium , Humans , Iontophoresis , Kidney , Kidney Failure, Chronic , Laser-Doppler Flowmetry , Magnesium , Microcirculation , Multivariate Analysis , Prospective Studies , Renal Dialysis , Renal Insufficiency, Chronic , Vasodilation
8.
Yonsei Medical Journal ; : 666-675, 2015.
Article in English | WPRIM | ID: wpr-93952

ABSTRACT

PURPOSE: The aim of this study was to investigate whether the survival rate among Korean dialysis patients changed during the period between 2005 and 2008 in Korea. MATERIALS AND METHODS: A total of 32357 patients who began dialysis between January 1, 2005 and December 31, 2008 were eligible for analysis. Baseline demographics, comorbidities, and mortality data were obtained from the database of the Health Insurance Review & Assessment Service. RESULTS: Kaplan-Meier curves according to the year of dialysis initiation showed that the survival rate was significantly different (log-rank test, p=0.005), most notably among peritoneal dialysis (PD) patients (p<0.001), although not among hemodialysis (HD) patients (p=0.497). In multivariate analysis, however, patients initiating either HD or PD in 2008 also had a significantly lower risk of mortality compared to those who began dialysis in 2005. Subgroup survival analysis among patients initiating dialysis in 2008 revealed that the survival rate of PD patients was significantly higher than that of HD patients (p=0.001), and the survival benefit of PD over HD remained in non-diabetic patients aged less than 65 years after adjustment of covariates. CONCLUSION: Survival of Korean patients initiating dialysis from 2005 to 2008 has improved over time, particularly in PD patients. In addition, survival rates among patients initiating dialysis in 2008 were different according to patients' age and diabetes, thus we need to consider these factors when dialysis modality should be chosen.


Subject(s)
Adult , Aged , Comorbidity , Female , Humans , Kaplan-Meier Estimate , Kidney Failure, Chronic/mortality , Male , Middle Aged , Multivariate Analysis , Peritoneal Dialysis/statistics & numerical data , Registries , Renal Dialysis/statistics & numerical data , Republic of Korea/epidemiology , Risk , Survival Analysis , Survival Rate/trends , Treatment Outcome
9.
Article in Korean | WPRIM | ID: wpr-146614

ABSTRACT

Patients with chronic renal failure (CRF) are known to be more susceptible to tuberculosis infection due to impairment of the host defense mechanism. Although extrapulmonary tuberculosis is more prevalent in those subjects and it may induce dismal outcome, its diagnosis has been challenging since there is no specific symptoms of the disease and the clinical course is usually atypical. Herein, We report a case of disseminated tuberculosis diagnosed by ultrasound-guided liver biopsy in a 31-year-old CRF patient presenting sustained fever despite broad-spectrum antimicrobial therapy and progressive cholestatic jaundice.


Subject(s)
Biopsy , Fever , Humans , Jaundice, Obstructive , Kidney Failure, Chronic , Liver , Tuberculosis
11.
Article in English | WPRIM | ID: wpr-195160

ABSTRACT

BACKGROUND/AIMS: Chronic inflammatory status is a possible risk factor for vascular access dysfunction in hemodialysis (HD) patients, but susceptibility differences appear among individuals. Interleukin (IL)-6 is a well-known inflammatory cytokine with various polymorphisms. We examined whether IL-6 polymorphisms are associated with vascular access dysfunction in HD patients. METHODS: A total of 80 HD patients (including 42 diabetic patients) were enrolled. Polymorphisms in the IL-6 gene promoter (-634 C/G and -174 G/C) were studied using restriction length polymorphism polymerase chain reaction analysis. Vascular access patency was compared between the patient groups with respect to IL-6 polymorphisms. An additional 89 healthy individuals were enrolled in the control group. Plasma IL-6 levels were de termined by enzyme-linked immunosorbent assay. RESULTS: The GG genotype and G allele at position -634 in the IL-6 promoter were more frequently observed in HD patients than in controls. Furthermore, the distribution of the -634 polymorphism differed according to vascular access patency in non-diabetic HD patients. However, the G allele was not a significant risk factor for early access failure. No significant association appeared between the IL-6 -634 C/G polymorphism and plasma IL-6 levels. The C allele of the IL-6 -174 G/C polymorphism was not detected in our study population. CONCLUSIONS: The IL-6 -634 G allele appears with greater frequently in patients with end-stage renal disease and may be associated with vascular access dysfunction in non-diabetic HD patients.


Subject(s)
Adult , Aged , Arteriovenous Shunt, Surgical/adverse effects , Asian Continental Ancestry Group/genetics , Case-Control Studies , Chi-Square Distribution , Enzyme-Linked Immunosorbent Assay , Female , Gene Frequency , Genotype , Graft Occlusion, Vascular/blood , Humans , Interleukin-6/blood , Kidney Failure, Chronic/blood , Logistic Models , Male , Middle Aged , Odds Ratio , Phenotype , Polymerase Chain Reaction , Polymorphism, Genetic , Promoter Regions, Genetic , Renal Dialysis , Republic of Korea , Time Factors , Treatment Outcome , Vascular Patency/genetics
12.
Article in English | WPRIM | ID: wpr-156024

ABSTRACT

BACKGROUND: Vascular access failure, a major cause of morbidity in hemodialysis (HD) patients, occurs mainly at stenotic endothelium following an acute thrombotic event. Microparticles (MPs) are fragments derived from injured cell membrane and are closely associated with coagulation and vascular inflammatory responses. METHODS: We investigated the relationship between levels of circulating MPs and vascular access patency in HD patients. A total of 82 HD patients and 28 healthy patients were enrolled. We used flow cytometry to measure endothelial MPs (EMPs) identified by CD31+CD42- or CD51+ and platelet-derived MPs (PMPs) identified by CD31+CD42+ in plasma samples of participants. Vascular access patency was defined as an interval from the time of access formation to the time of first access stenosis in each patient. MP counts were compared according to access patent duration. RESULTS: The levels of EMP (both CD31+CD42- and CD51+) and CD31+CD42+PMP were significantly higher in patients than in healthy participants. Levels of CD31+CD42-EMP and CD31+CD42+PMP showed a positive correlation. In nondiabetic HD patients, CD31+CD42-EMPs and CD31+CD42+PMPs were more elevated in the shorter access survival group (access survival or = 4 years). CONCLUSION: Elevated circulating EMP or PMP counts are influenced by end-stage renal disease and increased levels of EMP and PMP may be associated with vascular access failure in HD patients.


Subject(s)
Blood Platelets , Cell Membrane , Constriction, Pathologic , Endothelial Cells , Endothelium , Flow Cytometry , Humans , Kidney Failure, Chronic , Plasma , Renal Dialysis
13.
Article in English | WPRIM | ID: wpr-28041

ABSTRACT

We have hypothesized that non-dipper status and left ventricular hypertrophy (LVH) are associated with the development of chronic kidney disease (CKD) in non-diabetic hypertensive patients. This study included 102 patients with an estimated glomerular filtration rate (eGFR) > or = 60 mL/min/1.73 m2. Ambulatory blood pressure monitoring and echocardiography were performed at the beginning of the study, and the serum creatinine levels were followed. During the average follow-up period of 51 months, CKD developed in 11 patients. There was a significant difference in the incidence of CKD between dippers and non-dippers (5.0% vs 19.0%, P < 0.05). Compared to patients without CKD, patients with incident CKD had a higher urine albumin/creatinine ratio (52.3 +/- 58.6 mg/g vs 17.8 +/- 29.3 mg/g, P < 0.01), non-dipper status (72.7% vs 37.4%, P < 0.05), the presence of LVH (27.3% vs 5.5%, P < 0.05), and a lower serum HDL-cholesterol level (41.7 +/- 8.3 mg/dL vs 50.4 +/- 12.4 mg/dL, P < 0.05). Based on multivariate Cox regression analysis, non-dipper status and the presence of LVH were independent predictors of incident CKD. These findings suggest that non-dipper status and LVH may be the therapeutic targets for preventing the development of CKD in non-diabetic hypertensive patients.


Subject(s)
Adult , Aged , Aged, 80 and over , Albumins/analysis , Blood Pressure , Blood Pressure Monitoring, Ambulatory , Cholesterol, HDL/blood , Chronic Disease , Creatinine/blood , Cross-Sectional Studies , Female , Follow-Up Studies , Glomerular Filtration Rate , Humans , Hypertension/complications , Hypertrophy, Left Ventricular/complications , Incidence , Kidney Diseases/epidemiology , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies
14.
Article in Korean | WPRIM | ID: wpr-220805

ABSTRACT

PURPOSE: This study was aimed to compare hydration status between young and elderly end-stage renal disease (ESRD) patients on hemodialysis (HD) and to analyze factors related to overhydration. METHODS: We measured fluid status before a mid-week HD session in clinically stable 47 patients on maintenance HD using bioimpedance spectroscopy (BIS) device. In addition, weight and blood pressure (BP) were recorded during the treatment. RESULTS: Participants were divided into young ( or =65 years, n=15) patients. In elderly patients, pre-HD diastolic BP, intracellular water (ICW), and lean tissue index (LTI) were significantly lower and extracellular water (ECW)/total body water (TBW) was significantly higher than in young patients. However, there were no differences in pre-HD body mass index (BMI), ultrafiltration volume, pre-HD systolic BP, TBW, ECW, and fat tissue index between the two groups. ECW/TBW ratio and LTI were significantly correlated with age. In a multivariate regression analysis, age and pre-HD pulse pressure were significantly associated with ECW/TBW. CONCLUSION: Although BMI and TBW of elderly ESRD patients were similar to those of young patients, ICW and LTI were lower and ECW/TBW was higher in elderly patients than in young patients. Therefore, clinical manifestations related to overhydration may develop more frequently in elderly patients compared with young patients.


Subject(s)
Aged , Blood Pressure , Body Composition , Body Mass Index , Body Water , Edema , Humans , Kidney Failure, Chronic , Renal Dialysis , Spectrum Analysis , Ultrafiltration , Water
15.
Article in Korean | WPRIM | ID: wpr-229137

ABSTRACT

PURPOSE: Endothelial dysfunction is an event in the atherosclerotic process usually considered reversible at its early stage. Early detection, therefor, may improve the prognosis in the cardiovascular disease. The aim of this study was to investigate the vascular function in hemodialysis (HD) patients and to explore its relation to other various parameters with a specific emphasis on systemic inflammatory reaction (SIR), nutritional status and the presence of ischemic heart disease (IHD). METHODS: Flow-mediated endothelium-dependent vasodilatation (FMD) was measured, using Doppler sonogram, in 37 stable HD patients, 11 healthy people and 24 hypertensive controls. Nitroglycerine- induced endothelium-independent vasodilatation (EIV) and peak reaction time (PT) of each FMD and EIV were also measured. RESULTS: FMD in HD patients was decreased compared to healthy group whereas it was comparable in HD patients and hypertensive control. EIV in HD patients was significantly decreased compared to healthy and hypertensive controls. PT of each FMD and EIV was significantly delayed in HD patients. Each FMD and EIV showed a negative correlation with serum hsCRP level, but no significant correlations of FMD with other parameters were noted. Both FMD and EIV were further decreased in HD patients with IHD than non-IHD group. CONCLUSION: Our study confirmed a characteristic pattern of vascular dysfunction in HD patients: the impaired endothelial and smooth muscle function with a delayed reaction time. Importantly, SIR was one of the important factors determining vascular dysfunction in HD patients. Further studies will be necessary to define the causative role of SIR on endothelial dysfunction and the effect of inflammation- modulating therapy.


Subject(s)
C-Reactive Protein , Cardiovascular Diseases , Humans , Inflammation , Muscle, Smooth , Myocardial Ischemia , Nutritional Status , Prognosis , Reaction Time , Renal Dialysis , Vasodilation
16.
Article in Korean | WPRIM | ID: wpr-184046

ABSTRACT

PURPOSE: This study was undertaken to investigate the effect of a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor, FR167653, on urinary albumin excretion and on the expression of slit diaphragm-associated proteins in diabetic rats. METHODS: Thirty-two Sprague-Dawley rats were injected with diluent [control (C), N=16] or streptozotocin intraperitoneally (DM, N=16). Eight rats from each group were treated with 5 mg/kg/day FR 167653 (C+FR, DM+FR) for 6 weeks. At the time of sacrifice, 24-hour urinary albumin excretion was determined by ELISA. Glomerular nephrin, P-cadherin, and ZO-1 mRNA and protein expression were determined by real-time PCR and Western blot, respectively, with sieved glomeruli. RESULTS: Urinary albumin excretion was significantly higher in DM compared to C rats, and this increase in albuminuria was significantly inhibited by the administration of FR167653 in DM rats. Glomerular phospho-p38 MAPK protein expression was significantly increased in DM rats compared to C rats, and FR167653 treatment significantly attenuated the increase in phospho-p38 MAPK expression in DM glomeruli. Nephrin mRNA and protein expression were higher in 6-week DM compared to C glomeruli, and these increases were significantly abrogated with FR167653 treatment in DM rats. In contrast, FR167653 had no effects on the decrease in P-cadherin expression and the increase in ZO-1 expression observed in DM glomeruli. CONCLUSION: These findings suggest that FR167653, a p38 MAPK inhibitor, reduce the amount of albuminuria in early diabetic nephropathy, and this anti-proteinuric effect seems to be related with the change of glomerular nephrin expression.


Subject(s)
Albuminuria , Animals , Blotting, Western , Cadherins , Diabetic Nephropathies , Enzyme-Linked Immunosorbent Assay , Membrane Proteins , p38 Mitogen-Activated Protein Kinases , Protein Kinases , Proteins , Pyrazoles , Pyridines , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , RNA, Messenger , Streptozocin
17.
Article in Korean | WPRIM | ID: wpr-24730

ABSTRACT

PURPOSE: This study was undertaken to elucidate whether CC chemokine receptor 2 (CCR2) exists in human peritoneal mesothelial cells (HPMCs) and whether monocyte chemoattractant protein-1 (MCP-1) has direct effects on epithelial to mesenchymal transition (EMT) and fibronectin expression in HPMCs. METHODS: HPMCs were isolated from a piece of human omentum and were incubated with M199 media containing 5.6 mM glucose (LG), 5.6 mM glucose+94.4 mM mannitol (LG+M), LG+10 ng/mL recombinant human MCP-1 (LG+MCP-1), or 100 mM glucose (HG) with or without a specific inhibitor of CCR2, 1.0 micrometer RS102895, for 4 days. Levels of secreted MCP-1 in culture media were determined by ELISA. Western blot was performed to determine fibronectin, E-cadherin, alpha-smooth muscle actin (alpha-SMA) and CCR2 protein expression. RESULTS: MCP-1 protein levels were significantly increased in HG-conditioned media compared to LG media (p<0.05). CCR2 protein was expressed in HPMCs, but there was no difference between LGand HG-stimulated cells. alpha-SMA protein expressions in HG and LG+MCP-1 groups were significantly higher relative to LG cells, while E-cadherin protein expressions were decreased in HG and LG+ MCP-1 groups compared to LG cells (p<0.05). In addition, there were significant increases in fibronectin mRNA and protein expression in HG and LG+MCP-1 groups (p<0.05). These HG-induced changes were significantly abrogated upon pre-treatment with RS102895. CONCLUSION: HG and MCP-1 directly induce EMT and enhance fibronectin expression in HPMCs, and these HG-induced changes were attenuated by the inhibition of MCP-1/CCR2 system, suggesting that increased MCP-1 levels by HG may contribute to the development of peritoneal fibrosis.


Subject(s)
Actins , Blotting, Western , Cadherins , Chemokine CCL2 , Culture Media , Enzyme-Linked Immunosorbent Assay , Epithelial-Mesenchymal Transition , Fibronectins , Glucose , Humans , Mannitol , Monocytes , Muscles , Omentum , Peritoneum , Receptors, CCR2 , RNA, Messenger
18.
Article in Korean | WPRIM | ID: wpr-24722

ABSTRACT

Cyclosporine is one of the most useful immunosuppressants for many diseases including nephrotic syndrome, glomerulonephritis, organ transplantation, and other autoimmune diseases. However, cyclosporine is known to cause renal tubular acidosis (RTA) due to a decrease in urinary ammonium excretion. Cyclosporine also can lead to significant hypocitraturia due to a higher proximal tubular reabsorption of citrate and increase the risk for nephrolithiasis. Citrate excretion is essential for the prevention of urinary supersaturation and hypocitraturia is a major risk factor for nephrocalcinosis and nephrolithiasis. Now we report two cases of nephrolithiasis treated with cyclosporine. The first patient is a renal transplantation recipient and the second patient has membranous glomerulonephritis. Therefore, these two cases lead us to conclude that patients treated with cyclosporine have to be regularly followed up for nephrolithiasis caused by cyclosporine-induced tubular dysfunction.


Subject(s)
Acidosis, Renal Tubular , Autoimmune Diseases , Citric Acid , Cyclosporine , Glomerulonephritis , Glomerulonephritis, Membranous , Humans , Immunosuppressive Agents , Kidney Transplantation , Nephrocalcinosis , Nephrolithiasis , Nephrotic Syndrome , Organ Transplantation , Quaternary Ammonium Compounds , Risk Factors , Transplants
19.
Article in Korean | WPRIM | ID: wpr-9148

ABSTRACT

PURPOSE: Recently, many studies have investigated that Methylenetetrahydrofolate Reductase (MTHFR) polymorphism may be not a only cause for hyperhomocysteinemia, but also an independent risk factor for cardiovascular disease or atherosclerosis in renal failure patients. In this study, we analyzed MTHFR polymorphisms in chronic renal failure (CRF) patients, and investigated relationship between MTHFR polymorphism and peripheral atherosclerosis. METHODS: One hundred twenty eight CRF patients with GFR < 30 mL/min were enrolled. We analyzed their MTHFR polymorphism by standard PCR/restriction fragment length polymorphism and measured their ankle brachial index (ABI) using blood pressure cuff and Doppler stethoscope. Plasma homocysteine, vitamin B12, and folic acid levels were measured. 170 healthy peoples were enrolled for control group. RESULTS: The distribution of MTHFR 677 polymorphism of CRF patients was as follows: CC genotype, 33.6%; CT, 47.7% and TT 18.7%. Plasma homocysteine concentration was higher in TT group than in CC group (p < 0.05). The distribution of MTHFR 1298 polymorphism of CRF patients was as follows: AA type, 63.78%; AC, 33.07% and CC 18.7%. The distributions of MTHFR polymorphisms in control group were not different from patients group, respectively. There was no definite correlation between ABI and plasma homocysteine concentration. A trend of lower ABI in TT type compared with CC type within CRP patients group, but no statistical significance was shown. CONCLUSIONs: No difference of the distribution of MTHFR polymorphism was noted between CRF patients and healthy population. In CRF patients, MTHFR C677T mutation was closely associated with hyperhomocysteinemia, but both did not significantly influence to peripheral arterial disease.


Subject(s)
Ankle Brachial Index , Atherosclerosis , Blood Pressure , Cardiovascular Diseases , Folic Acid , Genotype , Homocysteine , Humans , Hyperhomocysteinemia , Kidney Failure, Chronic , Methylenetetrahydrofolate Reductase (NADPH2) , Peripheral Arterial Disease , Peripheral Vascular Diseases , Plasma , Renal Insufficiency , Risk Factors , Stethoscopes , Vitamin B 12
20.
Article in Korean | WPRIM | ID: wpr-15402

ABSTRACT

PURPOSE: Systemic inflammatory reaction (SIR) is an important determinant of cardiovascular (CV) mortality in CRF patients. UA is an end-product of purine metabolism, and recent studies have demonstrated that an elevated serum UA level is associated with an increased level of inflammatory mediators. Since hyperuricemia is one of the most prevalent complications in CRF and is linked to CV disease, we hypothesized hyperuricemia in CRF may play an important role in the development of CV disease by inducing SIR. METHODS: PBMCs were isolated by density gradient centrifugation in 21 CRF patients and age and sex-matched 20 healthy adults. CRP expression was evaluated by real time PCR and ELISA in PBMC stimulated with UA (0.3-12 mg/dL). RESULTS: There was no difference in constitutional CRP expression in PBMC from control and CRF patients. UA induced CRP mRNA (RT-PCR) and protein (ELISA) expression in PBMC, which was blocked by the organic anion transport inhibitor, probenecid (1 mM), suggesting entry of uric acid into cells was responsible for CRP expression. PBMC from CRF patients showed a significantly higher CRP production by UA compared to healthy control. There was no correlation between serum UA level and % increase in CRP production by UA. CONCLUSION: The exaggerated CRP expression by UA can be another mechanism of SIR and increased CV morbidity in CRF patients. Prospective studies with uric acid-lowering therapy are necessary to confirm clinical significance of these interesting in-vitro findings.


Subject(s)
Adult , C-Reactive Protein , Cardiovascular Diseases , Centrifugation, Density Gradient , Enzyme-Linked Immunosorbent Assay , Humans , Hyperuricemia , Inflammation , Metabolism , Mortality , Probenecid , Real-Time Polymerase Chain Reaction , RNA, Messenger , Uric Acid
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