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IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis, and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.
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In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide-linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02) (a) reduced serum levels of IgG anti-dsDNA, IL-1ß, IL-6, and TNF-α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF-κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf-02 significantly inhibited secretion of IL-1ß in lipopolysaccharide-stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf-02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf-02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome-driven signaling.
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Autofagia/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-1beta/imunologia , Nefrite Lúpica/tratamento farmacológico , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Células Dendríticas , Feminino , Humanos , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de SjogrenRESUMO
IgA nephropathy (IgAN), the most common primary glomerular disorder, has a relatively poor prognosis yet lacks a pathogenesis-based treatment. Compound K (CK) is a major absorbable intestinal bacterial metabolite of ginsenosides, which are bioactive components of ginseng. The present study revealed promising therapeutic effects of CK in two complementary IgAN models: a passively induced one developed by repeated injections of IgA immune complexes and a spontaneously occurring model of spontaneous grouped ddY mice. The potential mechanism for CK includes 1) inhibiting the activation of NLRP3 inflammasome in renal tissues, macrophages and bone marrow-derived dendritic cells, 2) enhancing the induction of autophagy through increased SIRT1 expression, and 3) eliciting autophagy-mediated NLRP3 inflammasome inhibition. The results support CK as a drug candidate for IgAN.
Assuntos
Autofagia/efeitos dos fármacos , Ginsenosídeos/farmacologia , Glomerulonefrite por IGA/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Sirtuína 1/metabolismo , Animais , Autofagia/imunologia , Linhagem Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Ginsenosídeos/uso terapêutico , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
The downregulation of melatonin receptor 1A (MTNR1A) is associated with a range of pathological conditions, including membranous nephropathy. Knowledge of the mechanism underlying MTNR1A expression has been limited to the transcriptional regulation level. Here, RNA interference screening in human kidney cells revealed that heterogeneous nuclear ribonucleoprotein L (hnRNPL) upregulated MTNR1A RNA post-transcriptionally. hnRNPL knockdown or overexpression led to increased or decreased levels of cyclic adenosine monophosphate-responsive element-binding protein phosphorylation, respectively. Molecular studies showed that cytoplasmic hnRNPL exerts a stabilizing effect on the MTNR1A transcript through CA-repeat elements in its coding region. Further studies revealed that the interaction between hnRNPL and MTNR1A serves to protect MNTR1A RNA degradation by the exosome component 10 protein. MTNR1A, but not hnRNPL, displays a diurnal rhythm in mouse kidneys. Enhanced levels of MTNR1A recorded at midnight correlated with robust binding activity between cytoplasmic hnRNPL and the MTNR1A transcript. Both hnRNPL and MTNR1A were decreased in the cytoplasm of tubular epithelial cells from experimental membranous nephropathy kidneys, supporting their clinical relevance. Collectively, our data identified cytoplasmic hnRNPL as a novel player in the upregulation of MTNR1A expression in renal tubular epithelial cells, and as a potential therapeutic target.
Assuntos
Citoplasma/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo L/metabolismo , Túbulos Renais/metabolismo , Receptor MT1 de Melatonina/genética , Animais , Linhagem Celular , Ritmo Circadiano/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Epiteliais/metabolismo , Exorribonucleases/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/patologia , Humanos , Túbulos Renais/patologia , Camundongos Endogâmicos BALB C , Modelos Biológicos , Fases de Leitura Aberta/genética , Fosforilação , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor MT1 de Melatonina/metabolismo , Sequências Repetitivas de Ácido Nucleico/genética , Regulação para Cima/genéticaRESUMO
Melatonin is a hormone majorly secreted by the pineal gland and contributes to a various type of physiological functions in mammals. The melatonin production is tightly limited to the AANAT level, yet the most known molecular mechanisms underlying AANAT gene transcription is limited in the pinealocyte. Here, we find that c-Fos and cAMP-response element-binding protein (CREB) decreases and increases the AANAT transcriptional activity in renal tubular epithelial cell, respectively. Notably, c-Fos knockdown significantly upregulates melatonin levels in renal tubular cells. Functional results indicate that AANAT expression is decreased by c-Fos and resulted in enhancement of cell damage in albumin-injury cell model. We further find an inverse correlation between c-Fos and AANAT levels in renal tubular cells from experimental membranous nephropathy (MN) samples and clinical MN specimens. Our finding provides the molecular basis of c-Fos in transcriptionally downregulating expression of AANAT and melatonin, and elucidate the protective role of AANAT in preventing renal tubular cells death in albumin-injury cell model and MN progression.
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Arilalquilamina N-Acetiltransferase/genética , Regulação para Baixo , Células Epiteliais/metabolismo , Glomerulonefrite Membranosa/genética , Proteínas Proto-Oncogênicas c-fos/genética , Animais , Arilalquilamina N-Acetiltransferase/metabolismo , Linhagem Celular , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glomerulonefrite Membranosa/metabolismo , Glomerulonefrite Membranosa/patologia , Células HEK293 , Humanos , Túbulos Renais/citologia , Melatonina/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativação TranscricionalRESUMO
INTRODUCTION: Patients with carbon monoxide poisoning (COP) commonly have long-term morbidities. However, it is not known whether patients with COP exhibit an increased risk of developing chronic kidney disease (CKD) and whether hyperbaric oxygen therapy (HBOT) alters this risk. METHODS: This study identified 8,618 patients who survived COP and 34,464 propensity score-matched non-COP patients from 2000 to 2013 in a nationwide administrative registry. The primary outcome was the development of CKD. The association between COP and the risk of developing CKD was estimated using a Cox proportional hazards regression model; the cumulated incidence of CKD among patients stratified by HBOT was evaluated using a Kaplan-Meier analysis. RESULTS: After adjusting for covariates, the risk of CKD was 6.15-fold higher in COP patients than in non-COP controls. Based on the subgroup analyses, regardless of demographic characteristics, environmental factors, and comorbidities, the COP cohort exhibited an increased risk of developing CKD compared with the controls. The cumulative incidence of CKD in COP patients did not differ between the HBOT and non-HBOT groups (p = 0.188). CONCLUSIONS: COP might be an independent risk factor for developing CKD. Thus, clinicians should enhance the postdischarge follow-up of kidney function among COP patients.
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Intoxicação por Monóxido de Carbono/complicações , Intoxicação por Monóxido de Carbono/terapia , Oxigenoterapia Hiperbárica , Insuficiência Renal Crônica/etiologia , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos , Medição de Risco , Taiwan , Adulto JovemRESUMO
The coronavirus disease 2019 (COVID-19) pandemic is the largest health crisis ever faced worldwide. It has resulted in great health and economic costs because no effective treatment is currently available. Since infected persons vary in presentation from healthy asymptomatic mild symptoms to those who need intensive care support and eventually succumb to the disease, this illness is considered to depend primarily on individual immunity. Demographic distribution and disease severity in several regions of the world vary; therefore, it is believed that natural inherent immunity provided through dietary sources and traditional medicines could play an important role in infection prevention and disease progression. People can boost their immunity to prevent them from infection after COVID-19 exposure and can reduce their inflammatory reactions to protect their organ deterioration in case suffering from the disease. Some drugs with in-situ immunomodulatory and anti-inflammatory activity are also identified as adjunctive therapy in the COVID-19 era. This review discusses the importance of COVID-19 interactions with immune cells and inflammatory cells; and further emphasizes the possible pathways related with traditional herbs, medications and nutritional products. We believe that such pathophysiological pathway approach treatment is rational and important for future development of new therapeutic agents for prevention or cure of COVID-19 infection.
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Tratamento Farmacológico da COVID-19 , Interações Hospedeiro-Patógeno , Medicina Tradicional , COVID-19/prevenção & controle , COVID-19/virologia , Quimioterapia Combinada , Humanos , Imunomodulação , Terapia de Alvo Molecular , Fitoterapia , Extratos Vegetais/uso terapêutico , SARS-CoV-2/fisiologia , Vitaminas/uso terapêutico , Zinco/uso terapêuticoRESUMO
Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed adaptive immunity. Reduced and delayed responses to interferons (IFN-I/IFN-III) can increase the synthesis of proinflammatory cytokines and extensive immune cell infiltration into the airways, leading to pulmonary disease. The development of effective treatments for severe COVID-19 patients relies on our knowledge of the pathophysiological components of this imbalanced innate immune response. Strategies to address innate response factors will be essential. Significant efforts are currently underway to develop vaccines against SARS-CoV-2. COVID-19 vaccines, such as inactivated DNA, mRNA, and protein subunit vaccines, have already been applied in clinical use. Various vaccines display different levels of effectiveness, and it is important to continue to optimize and update their composition in order to increase their effectiveness. However, due to the continuous emergence of variant viruses, improving the immunity of the general public may also increase the effectiveness of the vaccines. Many observational studies have demonstrated that serum levels of vitamin D are inversely correlated with the incidence or severity of COVID-19. Extensive evidence has shown that vitamin D supplementation could be vital in mitigating the progression of COVID-19 to reduce its severity. Vitamin D defends against SARS-CoV-2 through a complex mechanism through interactions between the modulation of innate and adaptive immune reactions, ACE2 expression, and inhibition of the renin-angiotensin system (RAS). However, it remains unclear whether Vit-D also plays an important role in the effectiveness of different COVID-19 vaccines. Based on analysis of the molecular mechanism involved, we speculated that vit-D, via various immune signaling pathways, plays a complementary role in the development of vaccine efficacy.
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Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Vitamina D/administração & dosagem , Vitamina D/sangue , Animais , COVID-19/sangue , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunogenicidade da Vacina , Pandemias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2/isolamento & purificação , Vitamina D/imunologiaRESUMO
Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN. Treatment of IgAN mice with Tris DBA resulted in markedly improved renal function, albuminuria and renal pathology, including glomerular cell proliferation, neutrophil infiltration, sclerosis and periglomerular inflammation in the renal interstitium, together with (Clin J Am Soc Nephrol. 2011, 6, 1301-1307) reduced mitochondrial ROS generation; (Am J Physiol-Renal Physiol. 2011. 301, F1218-F1230) differentially regulated autophagy and NLRP3 inflammasome; (Clin J Am Soc Nephrol. 2012, 7, 427-436) inhibited phosphorylation of JNK, ERK and p38 MAPK signalling pathways, and priming signal of the NLRP3 inflammasome; and (Free Radic Biol Med. 2013, 61, 285-297) blunted NLRP3 inflammasome activation through SIRT1- and SIRT3-mediated autophagy induction, in renal tissues or cultured macrophages. In conclusion, Tris DBA effectively ameliorated the mouse IgAN model and targeted signalling pathways downstream of ICs-mediated interaction, which is a novel immunomodulatory strategy. Further development of Tris DBA as a therapeutic candidate for IgAN is warranted.
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Autofagia/efeitos dos fármacos , Glomerulonefrite por IGA/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organometálicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Animais , Autofagia/genética , Biomarcadores , Biópsia , Modelos Animais de Doenças , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/etiologia , Imuno-Histoquímica , Testes de Função Renal , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Modelos Biológicos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Sirtuína 3/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
PURPOSE: To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. METHODS: We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). RESULTS: We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). CONCLUSIONS: Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.
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Amiodarona/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/efeitos adversos , Compostos de Sulfonilureia/efeitos adversos , Idoso , Estudos de Casos e Controles , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Revisão da Utilização de Seguros , Masculino , Vigilância da População , Fatores de Risco , Taiwan/epidemiologiaRESUMO
BACKGROUND: Acute water intoxication after hysteroscopy is a rare, life-threatening condition, often accompanied with delayed diagnosis owing to masked symptoms because of general anesthesia. CASE PRESENTATION: Herein we presented a 39-year-old female who presented with cardiac arrest after hysteroscopic myomectomy because of acute water intoxication and survived after extracorporeal membrane oxygenation, continuous venous-venous hemofiltration, and aggressive high sodium fluid resuscitation. CONCLUSION: Failure to recognize and treat this condition appropriately may lead to potentially lethal cardiopulmonary complications.
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Oxigenação por Membrana Extracorpórea , Parada Cardíaca/etiologia , Hipocinesia/diagnóstico por imagem , Complicações Intraoperatórias , Edema Pulmonar/diagnóstico por imagem , Irrigação Terapêutica/efeitos adversos , Miomectomia Uterina/efeitos adversos , Neoplasias Uterinas/cirurgia , Intoxicação por Água/complicações , Adulto , Terapia de Substituição Renal Contínua/métodos , Ecocardiografia , Feminino , Humanos , Histeroscopia , Gravidez , Tomografia Computadorizada por Raios X , Água , Intoxicação por Água/terapiaRESUMO
OBJECTIVE: Vitamin D has been demonstrated to lessen proteinuria severity in chronic kidney disease (CKD). Compared with healthy populations, patients with CKD may have lower serum levels of 1,25-dihydroxy vitamin D (1,25-(OH)2 D) and 25-hydroxy vitamin D (25-(OH) D). We investigated the effect of oral low-dose active vitamin D (calcitriol at 0.25 µg, 3 times weekly) on urinary protein excretion. DESIGN AND METHODS: We conducted a nonblinded and non-placebo-controlled study. In total, 60 patients with CKD (average estimated glomerular filtration rate of >15 mL/min) who received a stable dose of angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) were enrolled in this 24-week study. We randomly assigned these patients to the vitamin D group (oral calcitriol at 0.25 µg 3 times weekly with an ACEI or ARB) or the control group (ACEI or ARB). Change in the urine protein/creatinine ratio (uPCR) was the primary endpoint in this study. RESULTS: The mean baseline uPCRs of the 2 groups were comparable (1.84 ± 0.83 g/g vs. 2.02 ± 0.97 g/g, control vs. vitamin D group; P = .46). After the 24-week treatment, the uPCRs were significantly lower than the baseline values in the vitamin D group (1.35 ± 0.64 g/g; P < .05) but not in the control group. The values of uPCR decreased significantly at 8, 16, and 24 weeks (P < .05 vs. baseline) in the vitamin D group. The values of uPCRs were significantly lower in the vitamin D group than in the control group at 8, 16, and 24 weeks (P < .05). A positive correlation was discovered between reduction in uPCRs at 24-week and baseline 25-(OH) D serum level in the vitamin D group (r = 0.738, P < .001). CONCLUSION: Supplementary low-dose active vitamin D could reduce proteinuria in CKD patients with low serum 25-(OH) D levels.
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Insuficiência Renal Crônica , Deficiência de Vitamina D , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Calcitriol , Humanos , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Vitamina D , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/uso terapêuticoRESUMO
BACKGROUND: The recommended target low-density lipoprotein cholesterol (LDL-C) level for coronary artery disease (CAD) patients has been lowered from 100 to 70 mg/dL in several clinical guidelines for secondary prevention. We aimed to assess whether initiating statin treatment in CAD patients with baseline LDL-C 70-100 mg/dL in Taiwan could be cost-effective. METHODS: A Markov model was developed to simulate a hypothetical cohort of CAD patients with a baseline LDL-C level of 90 mg/dL. The incidence and recurrence of MI and stroke related to specific LDL-C levels as well as the statin effect, mortality rate, and health state utilities were obtained from the literature. The direct medical costs and rate of fatal events were derived from the national claims database. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was calculated, and sensitivity analyses were performed. RESULTS: Moderate-intensity statin use, a treatment regimen expected to achieve LDL <70 mg/dL in the base case, resulted in a net gain of 562 QALYs but with an additional expenditure of $11.4 million per 10,000 patients over ten years. The ICER was $20,288 per QALY gained. The probabilities of being cost-effective at willingness-to-pay thresholds of one and three gross domestic product per capita ($24,329 in 2017) per QALY were 51.1% and 94.2%, respectively. Annual drug cost was the most influential factor on the ICER. CONCLUSION: Lowering the target LDL-C level from 100 to 70 mg/dL among treatment-naïve CAD patients could be cost-effective given the health benefits of preventing cardiovascular events and deaths.
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Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , LDL-Colesterol , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/prevenção & controle , Análise Custo-Benefício , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Prevenção Secundária/economia , Taiwan/epidemiologiaRESUMO
Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Indicã/toxicidade , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Camundongos , Osteoclastos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , UbiquitinaçãoRESUMO
Renal osteodystrophy (ROD) represents bone disorders related to chronic kidney disease (CKD) and several bone biomarkers are used clinically to predict ROD in CKD and hemodialysis (HD) patients. Serum albumin associates with inflammation other than nutritional status in these patients. Chronic inflammation is proved to relate with bone loss, however, the influence of hypoalbuminemia on bone biomarkers is still unclear. In this study, we evaluated the pattern of bone biomarker changes and further studied the influence of hypoalbuminemia on these biomarkers. A total of 300 maintenance HD patients were evaluated and 223 HD patients were included in the study. The patients were grouped according to serum parathyroid hormone (PTH) levels (PTH ≤150 pg/mL, PTH 150-300 pg/mL, PTH 300-600 pg/mL and PTH >600 pg/mL). Bone biomarkers and inflammatory markers were measured and their relation with PTH levels was determined. Significantly increased interleukin-6 (IL-6) and lower albumin levels were noted among PTH>600 pg/mL group. Bone turnover markers were significantly higher in PTH >600 pg/mL group (p< 0.05). Hypoalbuminemia significantly increased the fibroblast growth factor-23 (FGF-23) and procollagen type 1N-terminal propeptide (P1NP) in PTH ≤150 pg/mL, PTH 150-300 pg/mL, PTH 300-600 pg/mL groups, whereas no such relation was noted among PTH> 600 ng/dL group. In conclusion, hypoalbuminemia represents a chronic inflammation which differently relates to bone turnover markers according to serum PTH levels in SHPT patients. Thus, serum albumin measurement should be considered in determining bone disorders among these patients.
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Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Hiperparatireoidismo/sangue , Hipoalbuminemia/sangue , Inflamação/sangue , Hormônio Paratireóideo/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Remodelação Óssea/genética , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Hiperparatireoidismo/complicações , Hiperparatireoidismo/patologia , Hipoalbuminemia/complicações , Hipoalbuminemia/patologia , Inflamação/complicações , Inflamação/patologia , Interleucina-6/sangue , Falência Renal Crônica , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Diálise Renal/efeitos adversos , Albumina Sérica/metabolismoRESUMO
Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/ß-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.
Assuntos
Reabsorção Óssea/metabolismo , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Cinacalcete/farmacologia , Osteoclastos/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Proteínas Wnt/metabolismo , Animais , Densidade Óssea , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Células Cultivadas , Cinacalcete/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismoRESUMO
Membranous nephropathy (MN), a type of glomerular nephritis, is one of the most common causes of nephrotic syndrome in adults. Although it is known that melatonin plays a protective role in MN, the role of melatonin receptors in the pathophysiology of MN is unclear. Using an experimental MN model and clinical MN specimens, we studied melatonin receptor expression and found that melatonin receptor 1A (MTNR1A) expression was significantly downregulated in renal tubular epithelial cells. Molecular studies showed that the transcription factor pituitary homeobox-1 (PITX1) promoted MTNR1A expression via direct binding to its promoter. Treatment of a human tubular cell line with albumin to induce injury resulted in the stable reduction in MTNR1A and PITX1 expression. PITX1 levels were significantly downregulated in tubular epithelial cells from mice MN kidneys and MN renal specimens. Knockdown of MTNR1A, PITX1, or cyclic adenosine monophosphate-responsive element-binding protein (CREB) decreased E-cadherin (CDH1) expression, but upregulated Per2 and α-smooth muscle actin (αSMA) expression. Blockade of the MTNR1A receptor with luzindole in MN mice further impaired renal function; this was accompanied by CDH1 downregulation and Per2 and αSMA upregulation. Together, our results suggest that in injured tissue, decreased PITX1 expression at the MTNR1A promoter regions leads to decreased levels of MTNR1A in renal tubular epithelial cells, which increases the future risk of MN.
Assuntos
Células Epiteliais/metabolismo , Glomerulonefrite Membranosa/metabolismo , Túbulos Renais/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Receptor MT1 de Melatonina/metabolismo , Animais , Imunoprecipitação da Cromatina , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Glomerulonefrite Membranosa/genética , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Regiões Promotoras Genéticas/genética , Interferência de RNARESUMO
BACKGROUND: Type 2 diabetes mellitus (DM) and associated complications are common in patients with chronic kidney disease (CKD) and can increase morbidity and mortality. A longitudinal 5-year observational study was conducted to investigate whether the use of anti-diabetic medications or not affected survival rates of diabetic dialysis patients. METHODS: Using a data sample of a million patients from Taiwan's National Health Insurance Database, a retrospective cohort study surveyed patients with type 2 DM who began dialysis between 2002 and 2007. The study population was classified into groups using or not using anti-diabetic drugs. The group using anti-diabetic drugs was then categorized into 3 subgroups, including use of only oral hypoglycemic agents (OHAs), only insulin, and OHAs-combined insulin groups. Subjects of these four groups were followed 5 years or to date of death. Three major areas were analyzed: (1) demographic data and medical history; (2) survival prognosis and causes of death; and (3) effects on survival prognosis of different classes of OHAs. RESULTS: A total of 912 patients fitting inclusion criteria were enrolled and followed-up for 5 years or to date of death. A total 465 patients died, and those not using anti-diabetic drugs (67.34 %) had a higher mortality rate than those using anti-diabetic drugs (46.42 %). After the multivariate analysis, group of OHAs-combined insulin had the lowest risk of death (HR 0.36, 95 % CI 0.27-0.47), followed by OHAs alone (HR 0.49, 95 % CI 0.38-0.63) and then insulin alone (HR 0.67, 95 % CI 0.51-0.88). To clarify four classes of OHAs (sulfonylurea, α-glucosidase inhibitors, meglitinide, and thiazolidinedione) are used in Taiwan for uremia patient with type 2 DM, and in our study, there were no significant differences in survival prognosis for the four drugs. Finally, the most common cause of death was infectious disease and there were no significant differences among the four groups. CONCLUSION: This 5-year observational study results suggested that diabetic dialysis patients with anti-diabetic drugs had a lower risk of death compared with those without anti-diabetic drugs. Despite insulin therapy, appropriate OHAs should play an important role in treating these patients.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/terapia , Hipoglicemiantes/uso terapêutico , Diálise Renal , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Distribuição de Qui-Quadrado , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Quimioterapia Combinada , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/classificação , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fatores de Proteção , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taiwan , Fatores de Tempo , Resultado do TratamentoRESUMO
Introduction Pulmonary embolism is a potentially life-threatening complication of nephrotic syndrome. Syncope is rarely reported as an initial presentation of pulmonary embolism in nephrotic patients. Case presentation We describe a 35-year-old man who was taking steroids and diuretics for relapse of minimal change disease who presented after a syncopal event. The patient was hypotensive and had distended neck veins. The major laboratory findings were hypoalbuminemia with mild proteinuria. The findings on electrocardiography, chest radiography, and echocardiography and the elevated plasma D-dimer level raised suspicion of pulmonary embolism. Thrombi in the bilateral main pulmonary arteries on chest computed tomography together with compromised hemodynamics were consistent with the diagnosis of massive pulmonary embolism. He received anticoagulant treatment and the disease resolved. Conclusion Pulmonary embolism should be considered as a cause of syncope in patients with nephrotic syndrome, despite the absence of severe hypoalbuminemia and proteinuria, especially in patients taking concurrent steroid and diuretic therapy.