Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 697
Filtrar
1.
Hum Immunol ; 82(3): 186-192, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33597097

RESUMO

BACKGROUND: Fc receptor-like (FCRL) molecules were considered to play a role in the pathogenesis of certain autoimmune diseases. Nonetheless, the clinical significance of FCRLs in IgA nephropathy (IgAN) remains unclear. OBJECTIVE: This study is aimed at investigating the expression levels of FCRLs molecules in IgAN patients and determining its relevance to disease activity. METHODS: The mRNA expression levels of FCRLs were determined in peripheral blood mononuclear cells (PBMCs) of 42 IgAN patients and 48 healthy controls by quantitative real-time PCR (qRT-PCR). FCRLs proteins expression in B cells of 25 IgAN patients, 14 patients with non-IgAN glomerulonephritis, and 29 healthy controls were detected by Flow cytometry. The Spearman correlation test was used to assess the correlation of FCRLs expression with clinical parameters of IgAN patients. RESULTS: Our results indicated significant down-regulation of FCRL2 and FCRL3 mRNA levels in IgAN patients compared to healthy subjects. Surface protein expression of FCRLs molecules confirmed the qRT-PCR results. But FCRL2 and FCRL3 protein levels did not correlate with clinicopathologic phenotypes of IgAN patients. However, we found a significant positively correlation of FCRL2 and FCRL3 mRNA expression with the core 1 ß1,3-galactosyltransferase (C1GALT1) and its molecular chaperone (Cosmc) mRNA levels in IgAN patients. CONCLUSIONS: FCRL2 and FCRL3 expression levels in IgAN patients are significantly decreased and correlated with CIGALT1 and Cosmc mRNA expression.


Assuntos
Glomerulonefrite por IGA/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Adulto , Células Cultivadas , Regulação para Baixo , Feminino , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Glomerulonefrite por IGA/genética , Humanos , Leucócitos Mononucleares/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Receptores de Superfície Celular/genética , Receptores Imunológicos/genética , Transcriptoma
2.
J Vis Exp ; (161)2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32716396

RESUMO

Immunoglobulin A (IgA) nephropathy is a type of primary glomerulonephritis characterized by the abnormal deposition of IgA, leading to the end-stage renal failure. In recent years, the involvement of microRNAs (miRNAs) has been reported in the pathogenesis of IgA nephropathy. However, there is no established method for profiling miRNAs in IgA nephropathy using small animal models. Therefore, we developed a reliable method for analyzing miRNA in the kidney of an IgA mouse model (HIGA mouse). The goal of this protocol is to detect the altered expression levels of miRNAs in the kidneys of HIGA mice when compared with the levels in kidneys of control mice. In brief, this method consists of four steps: 1) obtaining kidney samples from HIGA mice; 2) purifying total RNA from kidney samples; 3) synthesizing complementary DNA from total RNA; and 4) quantitative reverse transcription polymerase chain reaction (qRT-PCR) of miRNAs. Using this method, we successfully detected the expression levels of several miRNAs (miR-155-5p, miR-146a-5p, and miR-21-5p) in the kidneys of HIGA mice. This new method can be applied to other studies profiling miRNAs in IgA nephropathy.


Assuntos
Perfilação da Expressão Gênica/métodos , Glomerulonefrite por IGA/metabolismo , Imunoglobulina A/biossíntese , Rim/metabolismo , MicroRNAs/biossíntese , Animais , Modelos Animais de Doenças , Feminino , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/patologia , Imunoglobulina A/genética , Rim/patologia , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética
3.
Mol Med Rep ; 21(3): 1242-1250, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016442

RESUMO

Posttranslational modifications (PTMs) to histones such as lysine crotonylation are classified as epigenetic changes. Lysine crotonylation participates in various cellular processes and occurs in active promoters, directly accelerating transcription. The present study performed a proteomics analysis of crotonylation between healthy controls and patients with immunoglobulin A (IgA) nephropathy using tandem mass spectrometry and high­resolution liquid chromatography. The present results identified 353 crotonylated proteins and 770 modification sites, including 155 upregulated and 198 downregulated crotonylated proteins. In total, seven conserved motifs were identified in the present study. The present bioinformatics analysis results suggested a number of the crotonylated proteins exhibited various subcellular localization patterns, such as in the cytoplasm. Protein domains, including thioredoxin, moesin tail and myosin like IQ motif domains were markedly enriched in crotonylated proteins. Kyoto Encyclopedia of Genes and Genomes and functional enrichment analyses suggested significant enrichment of crotonylated proteins in complement and coagulation cascades, and antigen processing and presentation pathways displaying important relationships with IgA nephropathy. The present results suggested that crotonylation occurred in numerous proteins and may play key regulatory roles in IgA nephropathy.


Assuntos
Regulação da Expressão Gênica , Glomerulonefrite por IGA/metabolismo , Histonas/análise , Processamento de Proteína Pós-Traducional , Proteômica , Adulto , Motivos de Aminoácidos , Apresentação do Antígeno , Cromatografia Líquida , Biologia Computacional , Regulação para Baixo , Feminino , Glomerulonefrite por IGA/imunologia , Histonas/metabolismo , Humanos , Lisina/metabolismo , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Espectrometria de Massas em Tandem , Regulação para Cima
4.
Sci Rep ; 10(1): 492, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949193

RESUMO

Recent research has identified a population of PD-1hiCXCR5- 'peripheral helper' T (Tph) cells that simulate plasma cell differentiation by interactions between IL-21 and SLAMF5. However, the alteration of circulating Tph and CD138+ B in IgA nephropathy (IgAN) remains poorly understood. Flow cytometry analysis was used to measure the frequency of circulating PD-1hiCXCR5- T cells and CD138+ B cells in 37 patients with IgAN and 23 healthy controls (HCs). Estimated glomerular filtration rate (eGFR), 24 h urinary protein and serum cytokine concentrations were measured. The percentage of different subsets of circulating PD-1hiCXCR5- T cells and CD138+ B cells were significantly higher in patients with IgAN compared to HCs. Pretreatment, the percentage of different subsets of circulating PD-1hiCXCR5- T cells and CD138+ B cells were negatively correlated with eGFR, the percentage of circulating CD138+ B cells was positively correlated with 24-h urinary protein concentration, and the percentage of circulating PD-1hiCXCR5-, CD28+ and ICOS+ T cells. Posttreatment, the percentage of different subsets of circulating PD-1hiCXCR5- T cells and CD138+ B cells and serum IL-21 concentration were significantly reduced. Different subsets of circulating PD-1hiCXCR5- T cells contribute to the progression and pathogenesis of IgAN by regulating the differentiation of CD138+ B cells through a combination of surface molecules.


Assuntos
Linfócitos B/imunologia , Glomerulonefrite por IGA/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Adolescente , Adulto , Idoso , Benzazepinas/administração & dosagem , Benzazepinas/uso terapêutico , Estudos de Casos e Controles , Feminino , Glomerulonefrite por IGA/metabolismo , Humanos , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Sindecana-1/metabolismo , Valsartana/administração & dosagem , Valsartana/uso terapêutico , Adulto Jovem
5.
Mol Med Rep ; 21(2): 795-805, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974601

RESUMO

The aim of the present study was to investigate the involvement of B cell­activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor­associated factor 6 (TRAF6)/NF­κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)­short hairpin RNA (shRNA) (control group); con­shRNA + BAFF (20 ng/ml); con­shRNA + BAFF + BAFF­RFc chimera protein (500 µg/ml); TRAF6­shRNA; and TRAF6­shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague­Dawley rats were randomly divided into four groups: Con­small interfering RNA (siRNA) (control group); con­siRNA + IgA (IgA nephropathy group), BAFF­RFc chimera protein (2 µg/ml) + IgA, and TRAF6­siRNA (0.2 µM) + IgA. Reverse transcription­quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF­κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated­NF­κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF­κBP65 in glomerular mesangial cells. After the BAFF­RFc chimera protein was added to inhibit the binding of BAFF and BAFF­receptor (­R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF­R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway­associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF­κB signaling pathway.


Assuntos
Fator Ativador de Células B/metabolismo , Glomerulonefrite por IGA/metabolismo , Glomérulos Renais/patologia , Células Mesangiais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/metabolismo , Biomarcadores/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Creatinina/sangue , Feminino , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Glomerulonefrite por IGA/sangue , Humanos , Masculino , Células Mesangiais/patologia , Pessoa de Meia-Idade , Proteinúria/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Transcrição RelA/metabolismo
6.
Virchows Arch ; 476(6): 903-914, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31838587

RESUMO

IgA nephropathy (IgAN) is one of the most diffuse glomerulonephrites worldwide, and many issues still remain regarding our understanding of its pathogenesis. The disease is diagnosed by renal biopsy examination, but potential pitfalls still persist with regard to discriminating its primary origin and, as a result, determining patient outcome remains challenging. In this pilot study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was performed on renal biopsies obtained from patients with IgAN (n = 11) and other mesangioproliferative glomerulonephrites (MesPGN, n = 6) in order to enlighten proteomic alterations that may be associated with the progression of IgAN. Differences in the proteomic profiles of IgAN and MesPGN tissue could clearly be detected using this approach and, furthermore, 14 signals (AUC ≥ 0.8) were observed to have an altered intensity among the different CKD stages within the IgAN group. In particular, large increases in the intensity of these signals could be observed at CKD stages II and above. These signals primarily corresponded to proteins involved in either inflammatory and healing pathways and their increased intensity was localized within regions of tissue with large amounts of inflammatory cells or sclerosis. Despite much work in recent years, our molecular understanding of IgAN progression remains incomplete. This pilot study represents a promising starting point in the search for novel protein markers that can assist clinicians in better understanding the pathogenesis of IgAN and highlighting those patients who may progress to end-stage renal disease.


Assuntos
Biomarcadores/metabolismo , Glomerulonefrite por IGA/diagnóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Imunoquímica , Rim/metabolismo , Rim/patologia , Masculino , Projetos Piloto , Proteômica , Ucrânia , Vimentina/metabolismo , Adulto Jovem
7.
Acta Histochem ; 122(2): 151479, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31870504

RESUMO

AIM: Adverse and advanced prognostic signs in IgA nephropathy (IgAN) are interstitial fibrosis and tubular atrophy, but early predictors of bad outcome are still lacking. We investigated expression of connective tissue growth factor (CTGF) and c-Myb in renal biopsies of IgAN and Henoch-Schönlein purpura (HSP), because these gene products are indirectly included in fibrosis and epithelial-mesenchymal transition (EMT). METHODS: The sample included 23 patients and 8 controls who underwent nephrectomy due to renal cancer. The slides cut from the paraffin blocks were prepared for standard indirect immunoflourescence, using antibodies to CTGF and c-Myb. Ten high-power non-overlapping fields were photographed on Olympus IX51 microscope. Average percent of positive tubular cells, as well as number of positive cells per glomerulus were calculated. RESULTS: The cytoplasmic tubular CTGF expression was higher in IgAN/HSP than in controls (P < 0.001), whereas no difference was found in glomeruli (P = 0.437). The nuclear c-Myb expresssion in glomeruli and tubules was higher in IgAN/HSP than in controls (P < 0.05). In the follow-up, decline in renal function correlated with glomerular and tubular c-Myb, as well as tubular CTGF expression (all P < 0.05). CONCLUSION: Our results proposed c-Myb and CTGF as novel, early and sensitive markers of chronic kidney disease and worse renal outcome, but larger series are needed.


Assuntos
Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/metabolismo , Glomérulos Renais/metabolismo , Púrpura de Schoenlein-Henoch/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Criança , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
8.
Sci Rep ; 9(1): 20130, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882880

RESUMO

Streptococcus mutans is known to be a major causative agent of dental caries, and strains expressing the cell surface collagen-binding Cnm protein contribute to the development of several systemic diseases. A relationship between tonsillar immunity and glomerulonephritis has been recognized in IgA nephropathy (IgAN), and specific pathogens may have effects on tonsillar immunity (mucosal immunity). Here, we present findings showing a relationship between the presence of Cnm-positive S. mutans strains in the tonsils of IgAN patients and IgAN condition/pathogenesis. Analyses of tonsillar specimens obtained from patients with IgAN (n = 61) and chronic tonsillitis (controls; n = 40) showed that the Cnm protein-positive rate was significantly higher in IgAN patients. Among IgAN patients, the tonsillar Cnm-positive group (n = 15) had a significantly higher proportion of patients with high urinary protein (>1.5 g/gCr) and lower serum albumin level than the Cnm-negative group (n = 46). Additionally, Cnm protein and CD68, a common human macrophage marker, were shown to be merged in the tonsils of IgAN patients. These findings suggest that Cnm-positive S. mutans strains in the tonsils may be associated with severe IgAN.


Assuntos
Suscetibilidade a Doenças , Glomerulonefrite por IGA/etiologia , Tonsila Palatina/imunologia , Tonsila Palatina/microbiologia , Streptococcus mutans/imunologia , Adulto , Biomarcadores , Biópsia , Suscetibilidade a Doenças/imunologia , Feminino , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Tonsila Palatina/patologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Tonsilite/complicações , Tonsilite/imunologia , Tonsilite/microbiologia , Tonsilite/patologia
9.
Semin Immunol ; 45: 101331, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31711769

RESUMO

Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy.


Assuntos
Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Suscetibilidade a Doenças/imunologia , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Animais , Infecções Bacterianas/complicações , Biomarcadores , Ativação do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Glomerulonefrite/diagnóstico , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Glomerulonefrite Membranoproliferativa/etiologia , Glomerulonefrite Membranoproliferativa/metabolismo , Glomerulonefrite Membranoproliferativa/patologia , Síndrome Hemolítico-Urêmica/etiologia , Síndrome Hemolítico-Urêmica/metabolismo , Síndrome Hemolítico-Urêmica/patologia , Humanos
10.
Exp Cell Res ; 385(1): 111670, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600491

RESUMO

IgA nephropathy (IgAN) is a mesangial proliferative glomerulonephritis which often shows proteinuria, an indicator for podocyte damage. TGF-ß1 has been known to contribute to podocyte injury by inducing apoptosis, cytoskeleton relocation or cytoskeleton loss. And Decorin, a small proteoglycan known to neutralize TGF-ß1, was reported to induce autophagy in vascular endothelial cells. However, it remains unknown how TGF-ß1 and Decorin can affect podocyte autophagy in mesangial proliferative glomerulonephritis. In this study, we used in vivo and in vitro models to find out the effect of TGF-ß1 and Decorin on podocyte autophagy. P-rpS6 and p-ULK1 were detected by Western blot to show the activation of mTORC1 pathway following TGF-ß1 treatment. Also, we collected serum from IgAN patients and anti-Thy1.1 nephritis, and quantified TGF-ß1 and Decorin using ELISA. Together, we showed that TGF-ß1 could activate mTORC1 and inhibit autophagy, while Decorin has precisely the opposite effect. As the mesangial cells (MCs) proliferate, TGF-ß1 increases and Decorin decreases in the serum of IgAN and anti-Thy1.1 nephritis. This finding deepened our understanding regarding how MC proliferation could finally result in podocyte dysfunction.


Assuntos
Autofagia/fisiologia , Glomerulonefrite por IGA/metabolismo , Imunoglobulina A/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Proliferação de Células/fisiologia , Células Cultivadas , Citoesqueleto/metabolismo , Decorina/metabolismo , Células Endoteliais/metabolismo , Humanos , Masculino , Células Mesangiais/metabolismo , Podócitos/metabolismo , Ratos , Ratos Sprague-Dawley
11.
J Cell Mol Med ; 23(11): 7299-7309, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31557418

RESUMO

Peripheral blood mononuclear cells (PBMCs) play important roles in the pathogenesis of IgA nephropathy (IgAN). Our study aimed to provide a deep understanding of IgAN and focused on the dysregulation of hsa-miR-590-3p and its target gene HMGB2 in PBMCs. Three gene expression profile datasets (GSE14795, GSE73953 and GSE25590) were downloaded from the GEO database. The DEGs (differentially expressed genes)-miRNA network that was associated with IgAN was constructed by Cytoscape, and HMGB2 and hsa-miR-590-3p were selected for further exploration. The dual-luciferase reporter system was utilized to verify their interaction. Then, the expression levels of HMGB2 and hsa-miR-590-3p in PBMCs were detected by qPCR in another cohort, and the correlation of their expression levels with the clinical pathological manifestations and serum Gd-IgA1(galactose-deficient IgA1) levels was also investigated. HMGB2 was identified as the target gene of hsa-miR-590-3p. Furtherly, the elderly patients had higher HMGB2 expression levels than the expression levels of the younger patients. As the serum creatinine, serum BUN levels increased, the expression of HMGB2 decreased; Besides, the HMGB2 expression was positively correlated with serum complement 3(C3) levels, and it also had a negative correlation with the diastolic blood pressure, but not reach statistical significance. What is more, both hsa-miR-590-3p and HMGB2 expression had a slight correlation tendency with serum Gd-IgA1 levels in the whole population. In conclusion, HMGB2, the target gene of hsa-miR-590-3p, was identified to correlate with the severity of IgAN, and this provides more clues for the pathogenesis of IgAN.


Assuntos
Biomarcadores/metabolismo , Regulação da Expressão Gênica , Glomerulonefrite por IGA/patologia , Proteína HMGB2/metabolismo , MicroRNAs/genética , Índice de Gravidade de Doença , Adulto , Estudos de Coortes , Feminino , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/metabolismo , Proteína HMGB2/genética , Humanos , Masculino , Prognóstico , Transcriptoma
12.
J Autoimmun ; 105: 102309, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31402200

RESUMO

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a major cause of chronic kidney disease and failure. IgAN is driven by an autoimmune reaction against galactose-deficient IgA1 that results in the generation of autoantibodies and large IgG-IgA immune complexes. Immune complexes accumulate in the glomerular mesangium causing chronic inflammation and renal scarring. A significant proportion of IgAN patients develop end-stage kidney disease and require dialysis or transplantation. Currently, there are no approved specific therapies that can ameliorate the systemic autoimmune reaction in IgAN and no biomarkers that can predict renal inflammation and scarring. In this study, we used shotgun LC-MS/MS proteomics to compare small volumes of urine from healthy subjects and IgAN patients. We identified multiple urine proteins with unknown renal or IgAN function. Our attention was captured by the increase of phosphatidylethanolamine binding protein-4 (PEBP4) in IgAN urine. The function of PEBP4 in IgAN or renal disease is unknown. Increased levels of urine and serum PEBP4 were subsequently validated in different cohorts of IgAN patients and PEBP4 was linked to declining kidney function in IgAN. Strong PEBP4 staining was sporadically seen in IgAN kidney biopsies, colocalising with IgA in glomeruli and in the lumen of kidney tubules. In a small number of IgAN biopsies, PEBP4 colocalised with IgA and CD19 while the increased excretion of PEBP4 in IgAN urine was accompanied by increased excretion of classic B-cell factors BAFF, BCMA and TACI as well as IgA and IgG. PEBP4 is a new IgAN-related protein with unknown function and a likely renal disease marker in urine and serum.


Assuntos
Linfócitos B/imunologia , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/imunologia , Rim/imunologia , Proteína de Ligação a Fosfatidiletanolamina/imunologia , Adulto , Complexo Antígeno-Anticorpo/imunologia , Autoanticorpos/imunologia , Linfócitos B/metabolismo , Biomarcadores/metabolismo , Biópsia , Estudos de Casos e Controles , Feminino , Galactose/imunologia , Galactose/metabolismo , Mesângio Glomerular/imunologia , Mesângio Glomerular/metabolismo , Glomerulonefrite por IGA/metabolismo , Humanos , Rim/metabolismo , Falência Renal Crônica/imunologia , Falência Renal Crônica/metabolismo , Masculino
13.
BMC Nephrol ; 20(1): 320, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419951

RESUMO

BACKGROUND: The challenges in diagnosis of rare renal conditions can negatively impact patient prognosis, quality of life and result in significant healthcare costs. Differential methylation is emerging as an important biomarker for rare diseases and should be evaluated for rare renal conditions. METHODS: A comprehensive systematic review of methylation and rare renal disorders was conducted by searching the electronic databases MEDLINE, EMBASE, PubMed, Cochrane Library, alongside grey literature from GreyLit and OpenGrey databases, for publications published before September 2018. Additionally, the reference lists of the included papers were searched. Data was extracted and appraised including the primary focus, measurement and methodological rigour of the source. Eligibility criteria were adapted using the inclusion criteria from 'The 100,000 Genomes Project' and The National Registry of Rare Kidney Diseases, with additional focus on methylation. RESULTS: Thirteen full text articles were included in the review. Diseases analysed for differential methylation included glomerular disease, IgA nephropathy, ADPKD, rare causes of proteinuria, congenital renal agenesis, and membranous nephropathy. CONCLUSIONS: Differential methylation has been observed for several rare renal diseases, highlighting its potential for improving molecular characterisation of these disorders. Further investigation of methylation following a standardised reporting structure is necessary to improve research quality. Multi-omic data will provide insights for improved diagnosis, prognosis and support for individuals living and working with rare renal diseases.


Assuntos
Nefropatias/diagnóstico , Doenças Raras/diagnóstico , Biomarcadores/metabolismo , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/metabolismo , Humanos , Rim/anormalidades , Nefropatias/metabolismo , Metilação , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/metabolismo , Proteinúria/diagnóstico , Proteinúria/metabolismo , Doenças Raras/metabolismo
14.
Pediatr Int ; 61(11): 1133-1139, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31237969

RESUMO

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a major cause of end-stage renal disease. Complement activation via the lectin pathway influences outcomes in IgAN. We examined the association of glomerular C4d deposition with clinicopathological severity at diagnosis and the disappearance of proteinuria in Japanese pediatric IgAN patients. METHODS: We retrospectively analyzed 25 children newly diagnosed with IgAN at Hokkaido University Hospital. We evaluated glomerular C4d immunofluorescent staining at diagnosis. We compared clinical findings, pathological findings (based on Oxford classification), and the disappearance of proteinuria within 24 months after renal biopsy between C4d-positive and C4d-negative patients. RESULTS: Glomerular C4d staining was observed in 14 patients (56.0%). C4d-positive patients had significantly higher proteinuria at diagnosis than C4d-negative patients (2.03 g/gCr vs 0.78 g/gCr; P = 0.005). The number of glomeruli with segmental glomerulosclerosis or adhesion (8.0% vs 0.0%; P = 0.046) and the extent of tubular atrophy/interstitial fibrosis (9.46% vs 2.86%; P = 0.031) were significantly increased in C4d-positive patients compared with C4d-negative patients. Further, the proportion of patients with modified T1 (>10%) was significantly higher in the C4d-positive group than the C4d-negative group. There was no significant difference, however, in the disappearance rate of proteinuria at 24 months after renal biopsy between groups (64% vs 82%; P = 0.149). CONCLUSIONS: Glomerular C4d deposition was associated with clinicopathological severity at diagnosis in Japanese pediatric patients with IgAN. Glomerular C4d deposition, however, was not a predictor of the disappearance of proteinuria within 24 months after diagnosis in Japanese pediatric patients with IgAN.


Assuntos
Complemento C4b/metabolismo , Mesângio Glomerular/metabolismo , Glomerulonefrite por IGA/diagnóstico , Fragmentos de Peptídeos/metabolismo , Adolescente , Biomarcadores/metabolismo , Biópsia , Criança , Progressão da Doença , Feminino , Seguimentos , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/metabolismo , Humanos , Estudos Retrospectivos , Índice de Gravidade de Doença
15.
Pediatr Res ; 86(4): 485-491, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31086291

RESUMO

BACKGROUND: Animal models of nephrotic syndrome (NS) revealed that tight junction (TJ)-like structures are generated together with a concomitant decrease in slit diaphragms (SDs). Claudins (CLDNs) are capable of forming TJ strands and thereby the backbone of TJs. We showed the ectopic expression of CLDN2 in podocytes in pediatric NS, and detected its localization. METHODS: Renal frozen specimens were obtained by biopsy from 49 pediatric patients: 21 subjects with MCD, 18 with FSGS, and 10 with IgA nephritis (IgA-N). CLDN2 expression was observed by immunohistochemistry and the CLDN2-positive area was calculated. Moreover, its localization was detected using immunoelectron microscopy. RESULTS: CLDN2 is ectopically detected in cases with MCD and FSGS before remission. The CLDN2-stained region in MCD and FSGS glomeruli before remission was significantly greater than that after remission as well as in IgA-N patients. Immunoelectron microscopy revealed that CLDN2 was concentrated along newly formed TJs in podocytes. CONCLUSION: The same pathological findings in terms of ectopic CLDN2 expression in podocytes were shown in cases with MCD and FSGS before remission. Immunofluorescence and immunoelectron studies of CLDN2 appear to afford a powerful tool for the diagnosis of primary NS. In addition, CLDN2 expression level may be related to disease status.


Assuntos
Claudinas/metabolismo , Expressão Ectópica do Gene , Síndrome Nefrótica/metabolismo , Podócitos/metabolismo , Adolescente , Animais , Biópsia , Biópsia por Agulha , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Glomerulonefrite por IGA/metabolismo , Glomerulosclerose Segmentar e Focal , Humanos , Masculino , Nefrose Lipoide/metabolismo , Sangue Oculto , Proteinúria , Indução de Remissão , Junções Íntimas
16.
Transplant Proc ; 51(5): 1481-1487, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31084922

RESUMO

BACKGROUND: Glomerular deposition of IgA1 is a common feature of Henoch-Schönlein purpura nephritis (HSPN) and is indistinguishable from that seen in IgA nephropathy (IgAN). Serum IgA1 is abnormally O-glycosylated in IgA nephropathy, which may contribute to the development of glomerular injury. Abnormal O-glycosylated IgA1 was also detected in HSPN using lectin enzyme-linked immunosorbent assay; however, this method cannot provide the exact structural information of O-glycans. Mass spectrometry is an effective means of quantification of O-glycans, and there is no report to evaluate IgA1 O-glycans in HSPN using mass spectrometry. MATERIALS AND METHODS: We investigated O-glycosylation profile in serum IgA1 from 7 HSPN recipients, 26 IgAN recipients, 25 recipients with other kidney diseases (OKDs), and 26 normal healthy donors using mass spectrometry. RESULTS: Of the 14 GalNac-Gal combinations detected using mass spectrometry, the percentage of the only 6GalNAc-2Gal combination was significantly different between HSPN and IgAN. The percentage of GalNAc 3 in HSPN recipients was significantly higher than that in OKDs recipients and healthy donors (P = .0027 and P < .0001, respectively). Inversely, the percentage of GalNAc 5 in HSPN recipients was significantly lower than that in OKDs recipients and healthy donors (P = .0008, P < .0001, respectively). Moreover, the Gal content and the Gal/GalNAc ratio of HSPN recipients were significantly lower than OKDs recipients and healthy donors. CONCLUSIONS: Examination of Henoch-Schönlein purpura recipients revealed that the number of GalNAc fell and the Gal attachment to GalNAc was reduced compared to other kidney diseases and healthy donors. The IgA1 O-glycosylation profile of HSPN was very similar to that of IgAN.


Assuntos
Imunoglobulina A/química , Imunoglobulina A/metabolismo , Púrpura de Schoenlein-Henoch/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Acetilgalactosamina/análise , Acetilgalactosamina/metabolismo , Feminino , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Glicosilação , Humanos , Masculino , Púrpura de Schoenlein-Henoch/patologia
17.
Immun Inflamm Dis ; 7(2): 86-93, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30957421

RESUMO

INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. It is well known that upper respiratory tract infections, particularly acute tonsillitis, often worsen IgAN. Recent many clinical studies clearly show that tonsillectomy with steroid pulse therapy is the effective treatments for IgAN patients. Recently, the immunological evidence of association between tonsil and IgAN has been reported. METHODS: In this review, the mechanism underlying the onset of IgAN, as a tonsil-induced autoimmune/inflammatory syndrome (TIAS), is outlined with the main focus on the authors' research results. RESULTS: In the tonsils of patients with IgAN, hyperimmune response to the unmethylated deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) take place, resulting in hyperproduction of interferon-γ. The hyperproduction is followed by both overproduction of mutated IgA via B-cell activating factor (BAFF)/a proliferation-inducing ligand (APRIL)-mediated pathways and overexpression of T-cell receptor Vß6, CXCR3, and CX3CR1 on tonsillar T cells. These IgA and T cells home to the kidney via the systemic circulation, resulting in nephritis of IgAN. CONCLUSIONS: Scientific evidence supporting the use of tonsillectomy has gradually accumulated. We hope that many additional researchers will publish new evidence linking the tonsils and kidneys in the future.


Assuntos
Autoimunidade , Glomerulonefrite por IGA/etiologia , Tonsila Palatina/imunologia , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Imunidade nas Mucosas , Imunoglobulina A/biossíntese , Imunoglobulina A/imunologia , Tonsila Palatina/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
18.
PLoS One ; 14(2): e0211812, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785896

RESUMO

Subepithelial deposits are observed in rare adult IgA nephropathy (IgAN) cases and are a key diagnostic finding in IgA-dominant infection-related glomerulonephritis (IgA-IRGN). Sometimes, it is difficult to distinguish IgA-IRGN from IgAN without a precise clinical history. We hypothesized that some IgA-IRGN cases might be diagnosed as IgAN with subepithelial deposits (IgAN-SD) and aimed to clarify the significance of subepithelial deposits in patients diagnosed with IgAN. We examined 464 patients diagnosed with IgAN at Nagasaki University Hospital and affiliated hospitals between 1996 and 2013. The differences in clinicopathological findings between IgAN-SD and IgAN with no subepithelial deposits (IgAN-NSD) were investigated. In addition to clinical data and typical IgAN pathological features, we analyzed complement levels, immunoglobulin localization, light chain staining patterns, and intramembranous deposits. There were 214 men and 250 women with a mean age of 38.8 ± 18.3 years. Subepithelial deposition was observed in 51 patients (11%). Compared to patients with IgAN-NSD, those with IgAN-SD had significantly lower mean serum protein (6.4 g/dL vs. 6.7 g/dL; p = 0.02), albumin (3.7 g/dL vs. 3.9 g/dL; p = 0.02), and complement (C3) (94 mg/dL vs. 103 mg/dL; p = 0.02) levels. Diffuse mesangial hypercellularity (M) (65% vs. 45%; p<0.01), endocapillary hypercellularity: (E) (43% vs. 28%; p = 0.03), and IgA staining in the glomerular capillary wall (22% vs. 8%; p<0.01) were more common in patients with IgAN-SD. The incidence of light chain lambda predominance was lower in patients with IgAN-SD (47% vs. 63%; p = 0.03). Hump-shaped subepithelial deposits and intramembranous deposits were observed in nine and 17 patients with IgAN-SD, respectively. Patients with IgAN-SD tended to have the characteristics of IgA-IRGN rather than IgAN-NSD. Since the therapeutic strategies for IgA-IRGN differ from those for IgAN, we should review the clinical history and pay careful attention to the clinical course in cases with atypical findings, such as subepithelial deposits.


Assuntos
Imunoglobulina A/metabolismo , Glomérulos Renais , Adulto , Estudos Transversais , Feminino , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/ultraestrutura , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
FASEB J ; 33(4): 5181-5195, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30629456

RESUMO

Because the association between sphingosine 1-phosphate (S1P)/apolipoprotein M (ApoM) and chronic kidney diseases has not been established, we investigated the involvement of S1P/ApoM in the phenotypes of IgA nephropathy in hyper-IgA (HIGA) mice. The overexpression of ApoM in adenoviral gene transfer ameliorated the phenotypes of IgA nephropathy in HIGA mice, whereas the knockdown of ApoM with siRNA caused deterioration. When ApoM-overexpressing HIGA mice were treated with VPC23019, an antagonist against S1P receptor 1 (S1P1) and 3 (S1P3), we observed that the protective effects of ApoM were reversed, whereas JTE013, an antagonist against S1P2, did not inhibit the effects. We also found that S1P bound to albumin accelerated the proliferation of MES13 cells and the fibrotic changes of HK2 cells, which were inhibited by JTE013, whereas S1P bound to ApoM suppressed these changes, which were inhibited by VPC23019. These results suggest that S1P bound to ApoM possesses properties protective against the phenotypes of IgA nephropathy through S1P1 and S1P3, whereas S1P bound to albumin exerts deteriorating effects through S1P2. ApoM may be useful as a therapeutic target to treat or retard the progression of IgA nephropathy.-Kurano, M., Tsuneyama, K., Morimoto, Y., Nishikawa, M., Yatomi, Y. Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper-IgA mice.


Assuntos
Apolipoproteínas M/uso terapêutico , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/tratamento farmacológico , Imunoglobulina A/sangue , Lisofosfolipídeos/uso terapêutico , Esfingosina/análogos & derivados , Animais , Western Blotting , Linhagem Celular , Creatinina/sangue , Creatinina/urina , Feminino , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/urina , Imunoglobulina A/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esfingosina/uso terapêutico , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/metabolismo
20.
J Tradit Chin Med ; 39(3): 346-355, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-32186007

RESUMO

OBJECTIVE: To investigate the effect of mitofusin 2 (Mfn2) and its downstream signaling pathway on glomerular mesangial cells (GMCs) proliferation in IgA nephropathy (IgAN), as well as the mechanism of action of Jixuecao (Herba Centellae Asiaticae, HCA) in the treatment of IgAN. METHODS: Adenovirus-mediated Mfn2 gene transfection and Mfn2 expression were analyzed by real-time polymerase chain reaction (PCR) and Western blotting. IgA1 induced the proliferation of GMCs, which were then treated with HCA. Cell proliferation was detected with cell counting kit-8 (CCK-8), and Mfn2 expression was analyzed by real-time PCR and western blotting. An IgAN animal model was also established and treated with HCA. GMCs proliferation was detected by hematoxylin-eosin staining, mitochondrial structure was analyzed by electron microscopy, mitochondrial function was determined by the Clark oxygen electrode method, and the expression of Mfn2, Phospho-extracellular regulated protein kinases1/2 (P-ERK1/2), Cyclin-dependent kinase 2 (CDK2), Phospho-p27 (p-p27), and cyclin A was analyzed by Western blotting. RESULTS: In vitro, HCA inhibited GMCs in a concentration-dependent manner in association with the upregulation of Mfn2 expression. The overexpression of Mfn2 inhibited IgA1-induced GMCs proliferation and elevated the effect of HCA. In vivo, treatment with HCA could alleviate albuminuria and creatinine and GMCs proliferation. These effects were related to the upregulation of Mfn2, p-p27 and inhibition of p-ERK1/2, CDK2, and cyclinA. Mitochondrial swelling, vacuolar degeneration, and reduction of respiratory control rate were identified in IgAN, but HCA could improve the mitochondrial structure and function. CONCLUSION: HCA inhibited GMCs proliferation via the upregulation Mfn2 and the inhibition of Ras-Raf-ERK/MAPK. We revealed that changes of mitochondrial structure and function are associated with IgAN, but that HCA can improve these mitochondrial features.


Assuntos
Proliferação de Células/efeitos dos fármacos , GTP Fosfo-Hidrolases/metabolismo , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/metabolismo , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Proteínas Mitocondriais/metabolismo , Triterpenos/uso terapêutico , Adenoviridae/genética , Animais , Western Blotting , GTP Fosfo-Hidrolases/genética , Glomerulonefrite por IGA/genética , Imuno-Histoquímica , Masculino , Proteínas Mitocondriais/genética , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...