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BACKGROUND: Diabetic nephropathy (DN) is a main cause of chronic renal failure. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial injury remain unclear. We aim to identify key transcription factor genes involved in diabetic tubulointerstitial injury. METHODS: A microarray dataset (GSE30122) from Gene Expression Omnibus (GEO) was downloaded. A total of 38 transcription factor genes based on 166 differentially expressed genes (DEGs) were identified by UCSC_TFBS. RESULTS: The regulatory network showed connections between the top 10 transcription factors and their target DEGs. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of targeted DEGs indicated that extracellular space, extracellular exosome, cell surface and complement and coagulation cascades were most significantly enriched. Utilizing Nephroseq v5 online platform, the mRNA expression pattern analysis of transcription factor genes demonstrated that mRNA expression of CDC5, CEBPA, FAC1, HFH1, IRF1, NFE2 and TGIF1 increased in renal tubulointerstitium of DN patients compared with normal controls while that of CEBPB and FOXO4 decreased in renal tubulointerstitium of DN patients compared with normal controls. Correlation analysis between mRNA expression of transcription factor genes in renal tubulointerstitium and clinical features showed that AP1, BACH1, CDC5, FAC1, FOXD1, FOXJ2, FOXO1, FOXO4, HFH1, IRF1, POU3F2, SOX5, SOX9, RSRFC4, S8 and TGIF1 may be related to diabetic tubulointerstitial injury. CONCLUSIONS: (1) CDC5, FAC1, FOXO4, HFH1, IRF1 and TGIF1 may be key transcription factor genes. (2)Transcription factors involved in diabetic tubulointerstitial injury may become prospective targets for diagnosis and treatment of DN.
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Diabetes Mellitus , Nefropatías Diabéticas , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Perfilación de la Expresión Génica , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Análisis por Micromatrices , ARN Mensajero , Biología Computacional , Redes Reguladoras de Genes , Factores de Transcripción Forkhead/genética , Proteínas Represoras/genética , Proteínas de Homeodominio/genéticaRESUMEN
INTRODUCTION: Catheter-related blood stream infection (CRBSI), the most common complication of central vein catheter (CVC), was closely associated with high morbidity and mortality in hemodialysis (HD) patients. Conjunction with systemic antibiotic, antibiotic lock (ABL) is an important therapeutic option to salvage the catheter. With extra antimicrobial and biofilm removing properties, urokinase plasminogen activator (uPA)-based ABL could have a potential role in the treatment of CRBSI. OBJECTIVE: In this study, we aimed to explore effectiveness of uPA-based (ABL) on microorganisms embedded in biofilms in vitro and CVC salvage rate in HD patients with CRBSI. METHODS: In vitro, we induced biofilms formation on the surface of HD catheter by mimicking the development of CRBSI. Applying uPA with or without antibiotics on the kinds of microorganism biofilms to explore its antimicrobial and biofilm removing properties. In vivo, 86 HD patients diagnosed as CRBSI were retrospectively enrolled to see effectiveness of uPA-based ABL on catheter salvage rate as compare to heparin-based ABL. RESULTS: uPA was effect to Staphylococcus epidermidis biofilms compared to Staphylococcus aureus, Escherichia coli, and Candida albicans. Less biofilm residues made the regrowth of S. epidermidis also limited. The combination of uPA with antibiotic showed better antimicrobial and antibiofilm activity than uPA alone or heparin-based ABL in vitro and in vivo. Among HD patients, uPA-based ABL did not cause any obvious adverse affects, and it was more effective in treating coagulase-negative Staphylococci related CRBSI than other microorganisms. CONCLUSIONS: The combination of uPA and a therapeutic plasma concentration of sensitive antibiotic can work together to effectively remove coagulase-negative S. epidermidis embedded in biofilms in vitro. uPA-based ABL is safe and effective therapeutic intervention for HD patients with CRBSI, especially compared to heparin-based ABL.
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Bacterias/crecimiento & desarrollo , Fenómenos Fisiológicos Bacterianos , Biopelículas/crecimiento & desarrollo , Infecciones Relacionadas con Catéteres , Catéteres Venosos Centrales/microbiología , Desinfección , Diálisis Renal , Activador de Plasminógeno de Tipo Uroquinasa/administración & dosificación , Bacterias/clasificación , Infecciones Relacionadas con Catéteres/microbiología , Infecciones Relacionadas con Catéteres/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Diabetic nephropathy (DN) is a primary cause of renal failure. However, studies providing renal gene expression profiles of diabetic tubulointerstitial injury are scarce and its molecular mechanisms still await clarification. To identify vital genes involved in the diabetic tubulointerstitial injury, three microarray data sets from gene expression omnibus (GEO) were downloaded. A total of 127 differentially expressed genes (DEGs) were identified by limma package. Gene set enrichment analysis (GSEA) plots showed that sister chromatid cohesion was the most significant enriched gene set positively correlated with the DN group while retinoid X receptor binding was the most significant enriched gene set positively correlated with the control group. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included extracellular matrix organization, extracellular space, extracellular matrix structural constituent, and Staphylococcus aureus infection. Twenty hub genes from three significant modules were ascertained by Cytoscape. Correlation analysis and subgroup analysis between hub genes and clinical features of DN showed that ALB, ANXA1, APOH, C3, CCL19, COL1A2, COL3A1, COL4A1, COL6A3, CXCL6, DCN, EGF, HRG, KNG1, LUM, SERPINA3, SPARC, SRGN, and TIMP1 may involve in diabetic tubulointerstitial injury. ConnectivityMap analysis indicated the most significant three compounds are 5182598, thapsigargin and 5224221. In conclusion, this study may provide new insights into the molecular mechanisms underlying diabetic tubulointerstitial injury as well as potential targets for diagnosis and therapeutics of DN.
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Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Although intense efforts have been made to elucidate the pathogenesis, the molecular mechanisms of DN remain to be clarified. To identify the candidate genes in the progression of DN, microarray datasets GSE30122, GSE30528, and GSE47183 were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network was constructed and the module analysis was performed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. A total of 61 DEGs were identified. The enriched functions and pathways of the DEGs included glomerulus development, extracellular exosome, collagen binding, and the PI3K-Akt signaling pathway. Fifteen hub genes were identified and biological process analysis revealed that these genes were mainly enriched in acute inflammatory response, inflammatory response, and blood vessel development. Correlation analysis between unexplored hub genes and clinical features of DN suggested that COL6A3, MS4A6A,PLCE1, TNNC1, TNNI1, TNN2, and VSIG4 may involve in the progression of DN. In conclusion, DEGs and hub genes identified in this study may deepen our understanding of molecular mechanisms underlying the progression of DN, and provide candidate targets for diagnosis and treatment of DN.
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BACKGROUND: Aberrant O-glycosylation IgA1 production is a major factor in the pathogenesis of IgA nephropathy, but the underlying mechanism is still unclear. IgA1 glycosylation modification is in Golgi, and downregulation of the Golgi peripheral membrane protein Golgi matrix protein 130 (GM130) could lead to glycosylation deficiency. In this study, we aimed to explore the role of GM130 in glycosylate deficiency IgA1 (Gd-IgA1) production. METHODS: We enrolled 27 IgA nephropathy patients, 12 patients with chronic tonsillitis, 15 non-IgAN chronic kidney disease patients, and 15 healthy volunteers as healthy control. We explored GM130 expression in Tonsillar tissue by immunofluorescence staining and Western blotting and expression in peripheral blood mononuclear cells (PBMCs) by flow cytometry. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia Villosa lectin-binding assay. Real-time PCR and Western blot were used to analyze the levels of ß1,3-Gal transferase (C1GALT1) and ST6GalNAC2, respectively. To explore the contribution of GM130 in IgA1 O-glycosylation modification, cells were subjected to experiments for evaluation of GM130 silencing by GM130-siRNA transfection. RESULTS: GM130 expression was significantly decreased in tonsil tissues and PBMC of IgAN patients; the expression of C1GALT1 decreased and Gd-IgA1 level increased significantly in patients with IgAN patients. The expression of GM130 was negatively related to Gd-IgA1 production. By siRNA transfection, our results clearly indicated that the downregulation of GM130 can increase IgA1 O-glycosylation deficiency, which is thought to reduce C1GALT1 expression but not affect the expression of ST6GalNAC2. CONCLUSION: We identified and demonstrated that GM130 plays an important role in IgA1 O-glycans deficiency in IgAN patients, by negatively regulating C1GALT1 expression. We believe that this finding will provide theoretical foundations for a new mechanism of Gd-IgA1 production in IgAN patients.
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Galactosiltransferasas/metabolismo , Glomerulonefritis por IGA/inmunología , Inmunoglobulina A/metabolismo , Proteínas de la Membrana/deficiencia , Adolescente , Adulto , Autoantígenos/genética , Biopsia , Células Cultivadas , Niño , Regulación hacia Abajo , Femenino , Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/patología , Glicosilación , Humanos , Inmunoglobulina A/inmunología , Riñón/inmunología , Riñón/patología , Leucocitos Mononucleares , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Tonsila Palatina/inmunología , Tonsila Palatina/patología , Cultivo Primario de Células , ARN Interferente Pequeño/metabolismo , Sialiltransferasas/metabolismo , Adulto JovenRESUMEN
Renal ischemia-reperfusion injury (IRI), a major cause of acute kidney injury as well as a contributor to a rapid kidney dysfunction and high mortality rates, is a complex yet not fully understood process. Investigation on the underlying molecular mechanism including the inflammation initiation and progression can help to have a better understanding of the disease, and thereby lead to a potential therapeutic approach. We established renal IRI mouse model groups differing in their ages. These renal IRI mice were treated either only with si-nuclear receptor subfamily 4, group A, member 1 (NR4A1) or together with si-ß-catenin by tail vein injection to analyze the role of NR4A1 and ß-catenin in the development of renal IRI. Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were examined for renal function analysis. Levels of the apoptosis markers B-cell lymphoma-2 (Bcl-2), Bcl-2 associated protein X (Bax), and cleaved caspase-3 were determined. NR4A1 gene was up-regulated in the renal tissues of all mice with IRI, which showed a much higher level in the old mice with IRI. si-NR4A1 treatment resulted in reduced SCr and BUN levels and a decrease of cell apoptosis, indicated by lower expression of Bax and cleaved Caspase-3, while in contrast increased levels of Bcl-2 were detected. Interestingly, also the ß-catenin level was increased by knockdown of NR4A1. Furthermore, si-ß-catenin reversed the effect of knockdown of NR4A1, leading to aggravated renal function damage, severe pathological injury and increased apoptosis. Thus, silencing NR4A1 ameliorates renal IRI via ß-catenin signaling pathway activation. Down-regulated NR4A1 confirms renoprotective properties against renal IRI via the activation of ß-catenin signaling pathway in old mice.
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Apoptosis , Enfermedades Renales/prevención & control , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/antagonistas & inhibidores , Sustancias Protectoras/metabolismo , Daño por Reperfusión/prevención & control , beta Catenina/metabolismo , Animales , Modelos Animales de Enfermedad , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ratones , Ratones Endogámicos C57BL , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal , beta Catenina/genéticaRESUMEN
BACKGROUND: Despite the progression of dialysis techniques, the mortality of hemodialysis (HD) patients is still high in China. Here, a retrospective study was performed to investigate the neglected risk factors of all-cause mortality during maintenance HD (MHD). METHODS: We investigated 117 MHD patients who died between 2011 and 2016 in the Second Xiangya Hospital of Central South University HD center. In order to analyze the risk factors of 48 months all-cause death, the methods of Kaplan-Meier and Cox regression were used. RESULTS: Multivariate analyses of adjusted age and gender showed that MHD patients with estimated glomerular filtration rate <7 or >10 mL/min/1.73 m2 and anemia (hemoglobin <100 g/L) at the initiation of dialysis are independently associated with the higher death risk. Using central venous catheter vascular access, cerebrovascular comorbidities, diabetes, low-flux dialyzer, and dialysis frequency ≤2 times weekly were also the independent risk factors of death within 48 months. CONCLUSIONS: This study indicated that the status of HD initiation is a risk factor of long-term survival in MHD patients, which were usually ignored for lacking of nephrology care prior and could potentially be identified and modified to improve the survival prognosis. Video Journal Club "Cappuccino with Claudio Ronco" at https://www.karger.com/Journal/ArticleNews/223997?sponsor=52.
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Causas de Muerte , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Diálisis Renal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Femenino , Humanos , Estimación de Kaplan-Meier , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/epidemiología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Diálisis Renal/efectos adversos , Diálisis Renal/métodos , Análisis de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: To investigate the correlation of different types of urinary abnormalities or different proteinuria and hematuria with the pathological injury of kidney in IgA nephropathy with isolated hematuria and/or mild proteinuria.â© Methods: Patients with primary IgA nephropathy, isolated hematuria and/or mild proteinuria were enrolled in the Department of Nephrology, the Second Xiangya Hospital, Central South University from January 2013 to January 2018. According to the difference of red blood cell count in urinary sediment and quantitative of 24-hour urinary protein (24 h-UP) during renal biopsy, the patients were grouped in 3 ways: a simple hematuria group, a hematuria and proteinuria group, and a simple proteinuria group; a proteinuria I group, a proteinuria II group, and a proteinuria III group; a hematuria I group, a hematuria II group, and a hematuria III group. The clinical parameters such as age, mean arterial pressure, blood urea nitrogen, serum creatinine, blood uric acid, 24 h-UP, and renal pathological damage were compared.â© Results: A total of 157 patients met the inclusion criteria, including 71 males and 86 females. The most common pathological type was focal and/or segmental glomerulosclerosis. The Lee's classification were dominated by grade III and IV, and the renal pathological injury was heavy. Immunoglobulin deposition was dominated by simple IgA deposition. The most common fluorescence intensity of IgA deposition was +++. 97 (61.78%) patients were accompanied by complement deposition and were mainly composed of simple complement C3 deposition. There were 18 patients (11.47%) in the simple hematuria group, 111 patients (70.70%) in the hematuria and proteinuria group, and 28 patients (17.83%) in the simple proteinuria group. Compared with the simple hematuria group, the proportion of patients with mild injury was lower in the simple proteinuria group, and the proportion of patients with moderate-to-severe injuries was increased (χ2=7.053, P=0.008). Compared with the hematuria and proteinuria group, the proportion of patients with mild injury was lower in the simple proteinuria group, and the proportion of patients with moderate-to-severe injury was increased (χ2=4.294, P=0.038). Compared with the proteinuria I group, the proportion of patients with mild injury was lower in the proteinuria III group, and the proportion of patients with moderate-to-severe injury was increased (χ2=5.433, P=0.020). There was no significant difference in the proportion of patients with renal pathological injury among different hematuria groups (P>0.05).â© Conclusion: The clinical manifestations of patients with IgA nephropathy with hematuria and/or mild proteinuria are inconsistent with renal pathological damage. Some patients with mild clinical manifestations have severe renal pathological damage and the renal pathological damage is more serious in simple proteinuria. The more proteinuria, the heavier the renal pathological damage.
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Glomerulonefritis por IGA , Creatinina , Femenino , Hematuria , Humanos , Riñón , Masculino , ProteinuriaRESUMEN
BACKGROUND/AIMS: Tonsillectomy may be an important method to achieve a long-term remission of IgAN, but patients' physical status may limit their access to this surgery. We proposed an encouraging solution through inhibiting GADD34 expression in order to promote tonsillar mononuclear cells (TMCs) apoptosis and reduce nephropathic IgA secretion. METHODS: A total of 12 IgAN and 9 non-IgAN patients were involved from March 2015 to May 2016. After TMCs were extracted by density gradient centrifugation and stimulated by inactivated hemolytic streptococcus, the mRNA and protein expression of GADD34, GRP78, CHOP, Bcl-2, Bcl-XL, AID, Iα-Cα, and cleaved caspase-3 were examined by fluorescent RT-PCR and Western blotting. Guanabenz treatment and siRNA interference were applied to downregulate GADD34 in tonsillar mononuclear cells from IgAN patients, and P-eIF2α expression was examined by Western Blotting. Cell apoptosis was evaluated by Annexin V FITC/PI flowcytometry, and IgA secretion in cultural supernatant was inspected by enzyme linked immunosorbent assay. RESULTS: After stimulation, the expression of GADD34 was significantly increased in IgAN patients (P< 0.05). Cell apoptosis was mitigated and IgA secretion level was elevated (P< 0.05). To be noticed, CHOP expression had no significant difference between two groups. After guanabenz treatment and siRNA interference, a prolonged elevation of P-eIF2α expression was observed. Cell apoptosis was reinforced and IgA secretion level was decreased (P< 0.05). CONCLUSION: GADD34 may be a potential therapeutic target for IgAN treatment due to its effect on cell apoptosis.
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Apoptosis , Factor 2 Eucariótico de Iniciación/metabolismo , Proteína Fosfatasa 1/metabolismo , Adolescente , Adulto , Células Cultivadas , Chaperón BiP del Retículo Endoplásmico , Femenino , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/patología , Guanabenzo/farmacología , Proteínas de Choque Térmico/metabolismo , Humanos , Inmunoglobulina A/metabolismo , Masculino , Persona de Mediana Edad , Tonsila Palatina/citología , Tonsila Palatina/efectos de los fármacos , Tonsila Palatina/metabolismo , Fosforilación , Proteína Fosfatasa 1/antagonistas & inhibidores , Proteína Fosfatasa 1/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factor de Transcripción CHOP/metabolismo , Adulto JovenRESUMEN
Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected. Although AKI-to-CKD transition has been intensively studied, the information of AKI on CKD is very limited. Nonetheless, AKI, when occurring in patients with CKD, is known to be more severe and difficult to recover. CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of transforming growth factor-ß, p53, hypoxia-inducible factor, and major developmental pathways. At the cellular level, CKD is characterized by mitochondrial dysfunction, oxidative stress, and aberrant autophagy. At the tissue level, CKD is characterized by chronic inflammation and vascular dysfunction. These pathologic changes may contribute to the heightened sensitivity of, and nonrecovery from, AKI in patients with CKD.
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Lesión Renal Aguda/patología , Autofagia , Inflamación/patología , Mitocondrias/patología , Insuficiencia Renal Crónica/patología , Lesión Renal Aguda/etiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Metilación de ADN , Epigénesis Genética , Humanos , Riñón/irrigación sanguínea , Riñón/patología , Mitocondrias/metabolismo , Estrés Oxidativo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/genética , Factores de Riesgo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Urgent-start dialysis is a major problem for incident dialysis population. Urgent start on hemodialysis is associated with an increased risk of infectious or mechanical complications, and its mortality is equal to or higher than that of urgent start on peritoneal dialysis (PD). However, compared to patients starting PD in a planned setting, those on urgent-started PD have an increased risk of mechanical complications and lower technique survival. METHODS: In this study, 101 adult incident dialysis patients (≥18 years old) who underwent Tenckhoff catheter implantation were enrolled. All of the patients were grouped according to the urgent PD mode: the intermittent PD (IPD) or automatic PD (APD) group, and patients were followed for 1 year. The paired or independent t test was used to analyze the change of laboratory variables. Pearson chi-square test was applied to compare the short outcome between the 2 groups. RESULTS: When PD was treated for 7 days and 1 month, the APD group has the lower serum potassium and phosphorus levels than the IPD group. The incidence of catheter dysfunction was significantly lower in the APD group. The morbidity of infection associated with PD in the first year was lower in the APD group despite no significant difference existing. The technique survival and patient survival rate have no evident difference between the 2 groups. CONCLUSION: Compared to IPD, urgent start on APD could reduce the risk of mechanical complication, which could be considered a gentle, safe, and feasible alternative to urgent start on IPD.
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Atención Ambulatoria/métodos , Catéteres de Permanencia/efectos adversos , Fallo Renal Crónico/terapia , Diálisis Peritoneal/métodos , Complicaciones Posoperatorias/epidemiología , Estudios de Factibilidad , Femenino , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Diálisis Peritoneal/instrumentación , Diálisis Peritoneal/mortalidad , Fosfatos/sangre , Complicaciones Posoperatorias/etiología , Periodo Posoperatorio , Potasio/sangre , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Proteinuria and decline of renal function are associated with progression of kidney disease. The Renin Angiotensin Aldosterone System (RAAS) plays an important role in blood pressure regulation, fluid volume, and sodium balance. Overactivity of RAAS contributes to the pathogenesis of a variety of clinical conditions including progress of chronic kidney disease (CKD). This review summarizes the use of RAAS inhibitors as dual therapy or monotherapy in different stages of kidney disease. Experimental and clinical studies have demonstrated RAAS inhibitors prevent proteinuria, kidney fibrosis and slow decline of renal function and thus play a protective role in both early and end stages of kidney disease. While combination use of RAAS inhibitors showed higher efficiency compared with monotherapy, it is also associated with higher incidence of adverse events. Besides ACEI/ARBs, more mechanism research of mineralocorticoid receptor antagonists in kidney disease should be performed.
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Antagonistas de Receptores de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Hipertensión/tratamiento farmacológico , Insuficiencia Renal Crónica , Sistema Renina-Angiotensina/efectos de los fármacos , Progresión de la Enfermedad , Humanos , Administración del Tratamiento Farmacológico , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
BACKGROUND/AIM: Focal segmental glomerulosclerosis (FSGS) typically presents with nephrotic range proteinuria, which could eventually develop into end-stage renal disease. Resveratrol (RSV) is a natural polyphenol compound, which has been reported to suppress inflammatory response and renal interstitial fibrosis. This study is aimed at evaluating the renoprotective effect of RSV treatment on adriamycin-induced FSGS. METHODS: In Balb/c mice, adriamycin nephropathy was induced by adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then the mice were treated with RSV (40 mg/kg body weight) once daily by oral gavage, again starting on the day of adriamycin injection and continued for 6 weeks. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. RESULTS: When treated with adriamycin, the expressions of C3aR, C5aR, sphingosine kinase 1 (Sphk1), and soluble urokinase-type plasminogen activator receptor (suPAR) were upregulated, while RSV treatment could inhibit the expressions of C3aR, C5aR, Sphk1, and suPAR, eventually leading to anti-inflammatory and anti-fibrosis conditions. CONCLUSION: RSV attenuates adriamycin-induced FSGS through C3aR/C5aR-Sphk1 pathway.
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Doxorrubicina/farmacología , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estilbenos/farmacología , Animales , Antiinflamatorios/farmacología , Fibrosis/tratamiento farmacológico , Fibrosis/metabolismo , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Resveratrol , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Elevated circulating IgA complex deposits in the glomerular mesangium and causes resultant mesangial cell activation, eventually leading to the progression of IgA nephropathy (IgAN). Complement-C1q TNF-related protein 3 (CTRP3) is documented as a potential anti-inflammatory and anti-fibrotic mediator; however, its role in IgAN is unknown. METHODS: Serum polymeric IgA (pIgA) was isolated from patients with IgAN and healthy volunteers. Human mesangial cells (HMCs) were incubated with the isolated pIgA. The expression of CTRP3 and its effects on inflammatory cytokines and extracellular matrix were evaluated. RESULTS: Median circulating CTRP3 decreased in patients with IgAN compared to the controls, accompanied by the elevated serum and urine TGF-ß and IL-6. While urine CTRP3 in IgAN patients were comparable to that in healthy subjects. pIgA dose-dependently inhibited the expression of CTRP3 and HMC tolerated pIgA at 1.0 mg/ml, for which galactose-deficient IgA might be responsible. pIgA markedly increased IL-6 and TGF-ß in HMCs, which were suppressed after Ad-CTRP3 transfection. Additionally, CTRP3 significantly inhibited pIgA-stimulated HMC proliferation, cell cycle progression and synthesis of CTGF and fibronectin. Furthermore, we found that pIgA-treated HMC exhibited higher NF-954;B activity as reflected by the increased levels of nuclear p65. Moreover, Src activation and the subsequent Smad3 phosphorylation were significantly elevated in response to the stimulation with pIgA. However, NF-954;B activity and Smad3 signaling were inhibited after Ad-CTRP3 transfection in HMC. CONCLUSION: CTRP3 potentially targeted to NF-954;B and TGF-ß-Src-Smad3 signaling and exerted anti-inflammatory and anti-fibrotic roles to attenuate the progression of IgAN, which may represent a new strategy for the treatment of IgAN.
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Glomerulonefritis por IGA/metabolismo , Inmunoglobulina A/metabolismo , Factores de Necrosis Tumoral/metabolismo , Adulto , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Matriz Extracelular/metabolismo , Femenino , Humanos , Masculino , FN-kappa B/metabolismoRESUMEN
BACKGROUND: Immunoglobulin (Ig) A nephropathy (IgAN) is the xFB01;nding of immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. Increasing evidence suggested that retinoic acid (RA) signaling selectively induces IgA isotype switching and basic leucine zipper transcription factor, ATF-like (BATF) controls the global regulators of class switch recombination (CSR) in lymphocytes. Great effort has been paid to identify whether impaired immune regulation along the 'mucosa-bone marrow (BM) axis' play an important role in the pathogenesis of IgAN. METHODS: The aim of the study was to investigate the expression of all-trans-RA (ATRA) and BATF, and to identify their impact on IgA CSR in IgAN patients and rat animal models. Blood samples and tonsillar tissue specimens were obtained from 22 patients with IgAN and 24 patients with chronic tonsillitis as control. RESULTS: Immunohistochemical, RT-PCR and western blotting examination revealed that RA signaling and BATF productions are activated in IgAN patients compared with controls. Lipopolysaccharide and α-hemolytic streptococcus stimulation upregulated RA receptor (RAR) and BATF expression, promote IgA CSR and ATRA productions in tonsil mononuclear cells. RAR alpha (RARα) or BATF siRNA decreases IgA expression. We also built IgAN rat models and found that RARα, BATF and activation-induced cytidine deaminase were upregulated in the peripheral blood, spleen and BM. With ATRA (500 µg/kg body weight) treatment for 8 weeks, IgA deposition on glomeruli and mesangial cells proliferation increased. It also revealed that ATRA activated BATF and IgA CSR in vivo. CONCLUSION: These data point toward the role of RA signaling together with BATF in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with neoantigen results in impaired mucosal and systemic IgA responses.
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Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/sangre , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/metabolismo , Tonsila Palatina/metabolismo , Tretinoina/sangre , Adolescente , Adulto , Animales , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina A/metabolismo , Cambio de Clase de Inmunoglobulina , Glomérulos Renales/metabolismo , Lipopolisacáridos , Masculino , Células Mesangiales/fisiología , Persona de Mediana Edad , Tonsila Palatina/inmunología , Cultivo Primario de Células , Distribución Aleatoria , Ratas Sprague-Dawley , Receptor alfa de Ácido Retinoico/metabolismo , Transducción de Señal , Bazo/metabolismo , Adulto JovenRESUMEN
For maintenance hemodialysis (MHD) patients, the blood is in low hypercoagulable state due to the use of heparin or low molecular weight heparin during dialysis. It is not rare to see hematoma in the puncture site. In recent years, several cases have been reported of spontaneous kidney rupture, but no hip hematoma, let alone both occurred in succession. There was one MHD patient with spontaneous kidney bleeding and hip hematoma in our hospital in 2014, and we provided effective treatment and follow-up.
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Hematoma/etiología , Cadera/patología , Riñón/patología , Diálisis Renal/efectos adversos , Estudios de Seguimiento , Hematoma/inducido químicamente , Hematoma/patología , Hemorragia/inducido químicamente , Hemorragia/etiología , Humanos , Masculino , Persona de Mediana Edad , Rotura Espontánea/etiología , Resultado del TratamientoRESUMEN
AIMS: This study aimed to evaluate the extent of apoptosis of tonsillar mononuclear cells (TMCs) derived from patients with IgA nephropathy (IgAN) and the effects of triptolide (TP) on the apoptosis of these TMCs. METHODS: TMCs were isolated from tonsillar tissues of patients with IgAN or chronic tonsillitis (control group). Rates of TMCs apoptosis were measured by annexin V-fluorescein isocyanate (FITC)/propidium iodide (PI)-labeled flow cytometry (FCM). Expression levels of Bcl-2 family proteins were quantified by immunohistochemistry of fixed tonsillar sections and Western blot analyzes of TMCs lysates. TMCs from IgAN patients were treated 10, 20, or 30 ng/mL TP for 24 h and then evaluated for viability by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, for the percentage of apoptotic cells by FCM, and for the relative expression levels of Bcl-2 family proteins by Western blot analysis. RESULTS: Compared to TMCs from the control group, TMCs from the IgAN group demonstrated lower rates of apoptosis, higher expression levels of the anti-apoptosis proteins Bcl-2 and Bcl-xL, and lower expression levels of the pro-apoptosis protein Bax. Treatment of IgAN patient-derived TMCs with 10, 20, or 30 ng/mL TP for 24 h suppressed the viability and promoted the apoptosis of TMCs in a dose-dependent manner. Western blot analysis revealed a TP dose-dependent decrease in Bcl-2 and Bcl-xL expression levels, in parallel with increased Bax protein levels. CONCLUSION: TMCs from IgAN patients may be in a state of inhibited apoptosis mediated by Bcl-2 family proteins, which may be reversed by TP treatment.
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Diterpenos/uso terapéutico , Glomerulonefritis por IGA/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Leucocitos Mononucleares/efectos de los fármacos , Tonsila Palatina/inmunología , Fenantrenos/uso terapéutico , Adolescente , Adulto , Apoptosis/efectos de los fármacos , Células Cultivadas , Diterpenos/farmacología , Evaluación Preclínica de Medicamentos , Compuestos Epoxi/farmacología , Compuestos Epoxi/uso terapéutico , Femenino , Glomerulonefritis por IGA/inmunología , Humanos , Inmunosupresores/farmacología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Tonsila Palatina/metabolismo , Fenantrenos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Adulto JovenRESUMEN
BACKGROUND: The efficacy of tonsillectomy in immunoglobulin A nephropathy (IgAN) remains controversial. The aim of the study was to conduct a randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgAN. METHODS: We randomly selected 98 patients with biopsy-proven IgA nephropathy and randomly allocated to receive tonsillectomy combined with drug therapy (Group A) or drug therapy alone (Group B). The participating patients were entered into a 4-year single-center study. Remission and relapse rate were calculated for hematuria and proteinuria using the Kaplan-Meier method. RESULTS: No differences were found between the two groups in their baseline clinical and histological characteristics. Patients with tonsillectomy exhibited considerable improvement in the following aspects compared to those patients who did not undergo tonsillectomy: time to reach first remission (3.1 vs. 24.9 months, p < 0.001) for hematuria and (2.5 vs. 26.1 months, p < 0.001) for proteinuria, cumulative remission rate (91.8% vs. 46.9%, p < 0.001 by log-rank test) for hematuria and (95.9% vs. 51.0%, p < 0.001) for proteinuria, the duration of first remission (26.5 vs. 11.8 months, p = 0.0047) for hematuria and (23.5 vs. 10.5 months, p = 0.0012) for proteinuria, as well as lower relapse rate for hematuria and proteinuria in Group A. CONCLUSION: Our clinical data demonstrated that tonsillectomy could be beneficial for IgAN patients, particularly by contributing to faster and longer remission, as well as reducing the frequency of possible future relapses.
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Glomerulonefritis por IGA/cirugía , Tonsilectomía , Adulto , Femenino , Hematuria , Humanos , Masculino , Proteinuria , Recurrencia , Inducción de Remisión , Resultado del TratamientoRESUMEN
OBJECTIVE: To examine levels of M-type phospholipase A2 receptor (PLA2R) and its antibody in the patients with hepatitis B virus-associated membranous nephropathy (HBV-MN), and to explore the correlation of PLA2R with laboratory parameters and pathological characteristics.â© Methods: A total of 49 adult patients with biopsy-proved HBV-MN were enrolled in this study. Levels of anti-PLA2R antibody in serum and PLA2R in renal tissue were detected. Patients were assigned into two groups: a positive PLA2R group and a negative PLA2R group. Differences in laboratory parameters and pathological characteristics were compared between the two groups.â© Results: Of 49 patients with HBV-MN, 17 had positive PLA2R expression in renal tissues. In the positive PLA2R group, 10 patients were positive for serum anti-PLA2R antibody. Patients with positive PLA2R expression in renal tissues showed higher levels of 24 hour urinary protein [(4.6±3.9) g/d], serum HbsAg (70.5%) and renal HbsAg expression (71%), while lower level of serum albumin [(24.1±7.5) g/L] than those of the negative group.â© Conclusion: PLA2R is expressed in the renal tissues and serum anti-PLA2R antibody can be detected in some HBV-MN patients. Positive PLA2R expression in renal tissue might be related to HbsAg deposition in serum and renal tissues. Patients with positive PLA2R expression in renal tissue have more severe glomerular sclerosis.
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Glomerulonefritis Membranosa/genética , Antígenos de Superficie de la Hepatitis B/efectos adversos , Hepatitis B/complicaciones , Enfermedades Renales/etiología , Enfermedades Renales/genética , Enfermedades Renales/fisiopatología , Receptores de Fosfolipasa A2/fisiología , Adulto , Anticuerpos , Autoanticuerpos/genética , Autoanticuerpos/fisiología , Biopsia , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/etiología , Virus de la Hepatitis B , Humanos , Riñón/irrigación sanguínea , Riñón/química , Riñón/fisiopatología , Masculino , Pronóstico , Proteinuria/epidemiología , Proteinuria/genética , Receptores de Fosfolipasa A2/sangre , Albúmina Sérica/genéticaRESUMEN
BACKGROUND: Immunoglobulin class-switch recombination (CSR) is crucial for the expression of IgA, and it plays a vital role in the physiopathology of IgA nephropathy (IgAN). The aim of the study is to investigate the effect of polyriboinosinic:polyribocytidylic acid (poly(I:C)) in modulating toll-like receptor (TLR) 3-B-cell-activating factor belonging to the TNF family (BAFF) axis activation, which in turn promotes IgA CSR of IgAN patients and the IgAN rat model. METHODS: Blood samples and tonsillar tissue specimens were obtained from 24 patients with IgAN and 26 patients with chronic tonsillitis as control. We also used the IgAN rat model to investigate the relationship between viral infection and IgA CSR. RESULTS: Immunohistochemical and ELISA western blotting examination revealed that the TLR3/BAFF axis is activated in IgAN patients when compared to controls. Synthetic double-stranded RNA poly(I:C) stimulation upregulates the TACI/TLR3/TRIF/TRAF6 expression and promotes IgA CSR and BAFF productions in tonsil mononuclear cells. TLR3 or BAFF siRNA decreases IgA expression. In IgAN rat models, TLR3/BAFF signaling was highly activated. With 200 µg poly(I:C) sodium salt into the left naris for 8 weeks, IgA was highly deposited on glomeruli. It also revealed that poly(I:C) activated TLR3/BAFF axis and IgA CSR in vivo. CONCLUSION: These data points toward the role of TLR3/BAFF axis in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with virus infection results in impaired mucosal and systemic IgA responses.