RESUMO
Astragaloside IV(AS-IV), a saponin purified from Astragalus membranaceus (Fisch.) Bge.var.mongholicus (Bge.) Hsiao, has been widely used in traditional Chinese medicine. However, the underlying mechanisms in treating chronic glomerular nephritis (CGN) have not been fully understood. The aim of the present study was to evaluate the potential mechanism of AS-IV on CGN. CGN rats were administrated with AS-IV at 10 mg·kg-1 ·d-1 (ASL) and 20 mg·kg-1 ·d-1 (ASH). Twenty four hour proteinuria, blood urea nitrogen (BUN), and serum creatinine (SCr) were detected. Hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining were performed to evaluate the kidney lesion. Transmission electron microscope and GFP-RFP-LC3 transfection assay were used to monitor the effect of AS-IV on autophagy. IL-6 and IL-1ß were detected. The expression of CyclinD1, PI3K/AKT/AS160 pathway and autophagy related proteins were detected by Western Blot. The results demonstrated that AS-IV improved kidney function, ameliorated kidney lesion, and diminished inflammatory in CGN rats. Further, both in vivo and vitro study demonstrated that AS-IV inhibited the proliferation of mesangial cells. AS-IV further displayed a remarkable effect on inhibiting the activation of PI3K/AKT/AS160 pathway and improved the activation of autophagy in vivo and vitro. These results suggested that AS-IV is a potential therapeutic agent for CGN and merits further investigation.
Assuntos
Autofagia/efeitos dos fármacos , Glomerulonefrite/prevenção & controle , Insuficiência Renal Crônica/prevenção & controle , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Astragalus propinquus/química , Células Cultivadas , Citoproteção/efeitos dos fármacos , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Ectopic lymphoid structures (ELS) consist of B-cell and T-cell aggregates that are initiated de novo in inflamed tissues outside of secondary lymphoid organs. When organized within follicular dendritic cell (FDC) networks, ELS contain functional germinal centers that can yield autoantibody-secreting plasma cells and promote autoimmune disease. Intranasal instillation of lupus-prone mice with crystalline silica (cSiO2), a respirable particle linked to human lupus, triggers ELS formation in the lung, systemic autoantibodies, and early onset of glomerulonephritis. Here we tested the hypothesis that consumption of docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid with anti-inflammatory properties, influences the temporal profile of cSiO2-induced pulmonary ectopic germinal center formation and development of glomerulonephritis. Female NZBWF1 mice (6-wk old) were fed purified isocaloric diets supplemented with 0, 4, or 10 g/kg DHA - calorically equivalent to 0, 2, or 5 g DHA per day consumption by humans, respectively. Beginning at age 8 wk, mice were intranasally instilled with 1 mg cSiO2, or saline vehicle alone, once per wk, for 4 wk. Cohorts were sacrificed 1, 5, 9, or 13 wk post-instillation (PI) of the last cSiO2 dose, and lung and kidney lesions were investigated by histopathology. Tissue fatty acid analyses confirmed uniform dose-dependent DHA incorporation across all cohorts. As early as 1 wk PI, inflammation comprising of B (CD45R+) and T (CD3+) cell accumulation was observed in lungs of cSiO2-treated mice compared to vehicle controls; these responses intensified over time. Marked follicular dendritic cell (FDC; CD21+/CD35+) networking appeared at 9 and 13 wk PI. IgG+ plasma cells suggestive of mature germinal centers were evident at 13 wk. DHA supplementation dramatically suppressed cSiO2-triggered B-cell, T-cell, FDC, and IgG+ plasma cell appearance in the lungs as well as anti-dsDNA IgG in bronchial lavage fluid and plasma over the course of the experiment. cSiO2 induced glomerulonephritis with concomitant B-cell accumulation in the renal cortex at 13 wk PI but this response was abrogated by DHA feeding. Taken together, realistic dietary DHA supplementation prevented initiation and/or progression of ectopic lymphoid neogenesis, germinal center development, systemic autoantibody elevation, and resultant glomerulonephritis in this unique preclinical model of environment-triggered lupus.
Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Centro Germinativo , Glomerulonefrite , Pulmão , Lúpus Eritematoso Sistêmico , Dióxido de Silício/toxicidade , Animais , Feminino , Centro Germinativo/imunologia , Centro Germinativo/patologia , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Pulmão/imunologia , Pulmão/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/prevenção & controle , CamundongosRESUMO
The interleukin (IL)12 family cytokines have been examined as therapeutic targets in the treatment of several autoimmune diseases. Our previous study showed that a novel IL12 family cytokine, IL39 (IL23p19/Ebi3) mediates inflammation in lupuslike mice. In the present study, the effect of antimouse IL39 polyclonal antibodies on autoimmune symptoms in lupuslike mice was investigated. Rabbit antimouse IL39 polyclonal antibodies were produced by immunization with recombinant mouse IL39, and purified using protein A chromatography. These antibodies were subsequently used to treat lupuslike mice. Flow cytometry, captured images, ELISA and H&E staining were used to determine the effect of antiIL39 polyclonal antibodies on inflammatory cells, autoantibody titers, proteinuria, infiltrating inflammatory cells and the structure of the glomerular region. The antiIL39 polyclonal antibodies effectively reduced the numbers of inflammatory cells, splenomegaly, autoantibody titers, proteinuria, infiltrating inflammatory cells, and restored the structure of the glomerular region in MRL/lpr mice. Taken together, these results suggested that antiIL39 polyclonal antibodies ameliorated autoimmune symptoms in lupuslike mice. Therefore, IL39 may be used as a possible target for the treatment of systemic lupus erythematosus.
Assuntos
Anticorpos/farmacologia , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Anticorpos/uso terapêutico , Autoanticorpos/sangue , Avaliação Pré-Clínica de Medicamentos , Feminino , Glomerulonefrite/etiologia , Glomerulonefrite/imunologia , Glomerulonefrite/prevenção & controle , Fatores Imunológicos/uso terapêutico , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor/imunologia , Proteinúria/etiologia , Proteinúria/imunologia , Proteinúria/prevenção & controle , Coelhos , Receptores de Citocinas/antagonistas & inibidores , Receptores de Citocinas/imunologiaRESUMO
Obesity is a major risk factor for the development of chronic kidney disease, even independent of its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding of obesity-related kidney disease is glomerulopathy, with glomerular hypertrophy, mesangial matrix expansion, and focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition of AMP kinase, and endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure in glomerular endothelial cells, podocytes, and proximal tubular epithelial cells after 28 weeks of a high-fat diet in C57BL/6 mice. Treatment with SS-31, a tetrapeptide that targets cardiolipin and protects mitochondrial cristae structure, during high-fat diet preserved normal mitochondrial structure in all kidney cells, restored renal AMP kinase activity, and prevented intracellular lipid accumulation, endoplasmic reticulum stress, and apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, SS-31 prevented loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-ß) cytokines. Thus, mitochondria protection can overcome lipotoxicity in the kidney and represent a novel upstream target for therapeutic development.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Glomerulonefrite/prevenção & controle , Túbulos Renais Proximais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Capilares/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Glomerulonefrite/etiologia , Túbulos Renais Proximais/ultraestrutura , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mitocôndrias/ultraestrutura , Obesidade/complicações , Oligopeptídeos/farmacologia , Podócitos/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Abelmoschus manihot (L.) medic (AM) is a natural medicinal plant used for the treatment of chronic kidney disease (CKD) in China. Huangkui capsule (HKC), an extract from AM, has been proved clinically effective in improving renal inflammation and glomerular injury in CKD. However, the mechanisms of HKC are still not fully understood. AIM OF THE STUDY: Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes and diabetic nephropathy (DN). This study evaluated the function of Huangkui capsule (HKC), an extract from Abelmoschus manihot (L.) medic (AM), as a dual agonist for PPARα/γ and investigated its anti-DN effects in a DN rat model. MATERIALS AND METHODS: ChIP and reporter gene assays were performed and the expression of PPARα/γ target genes was monitored to examine the ability of HKC to activate PPARα/γ. DN was induced in male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin. HKC was administered to the diabetic nephropathy rats at three different doses: high dose HKC (300mg/kg/d); middle dose HKC (175mg/kg/d); and low dose HKC (75mg/kg/d). Irbesartan (4mg/kg/d body weight) was used as a positive control. Following 12 weeks' treatment, we measured general status, renal morphological appearance, proteinuria, blood biochemical parameters, and glomerular morphological changes. The expression of collagen IV, TGFß, TNFα and IL-6 in renal tissue was evaluated. Endoplasmic reticulum (ER) stress in renal tissue was also analyzed. RESULTS: HKC enhanced the transcriptional activity of PPARα and PPARγ in cultured cells, livers and kidneys of DN rats, and it reduced serum triglyceride and cholesterol levels and fat in livers of DN rats. Furthermore, HKC reduced the expressions of inflammatory genes in kidneys of DN rats. Strikingly, HKC reduced ER stress and c-Jun NH2-terminal kinase activation in the liver and kidney of DN rats and subsequently improved renal injury. CONCLUSIONS: Our results show that HKC improved lipid metabolic disorders by activating PPARα/γ and attenuating ER stress. HKC could dose-dependently ameliorate renal inflammation and glomerular injury in DN rats. These results suggest that HKC has potential as an anti-DN agent for the treatment of DN in humans.
Assuntos
Abelmoschus/química , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Rim/efeitos dos fármacos , PPAR alfa/agonistas , PPAR gama/agonistas , Extratos Vegetais/farmacologia , Administração Oral , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Compostos de Bifenilo/farmacologia , Cápsulas , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/isolamento & purificação , Regulação da Expressão Gênica , Glomerulonefrite/metabolismo , Glomerulonefrite/prevenção & controle , Células HEK293 , Células Hep G2 , Humanos , Irbesartana , Rim/metabolismo , Rim/patologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Nefrectomia , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Plantas Medicinais , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Tetrazóis/farmacologia , TransfecçãoRESUMO
BACKGROUND: Although it has been shown that a vagus nerve stimulation of brain dead (BD) donors leads to an improvement of renal function in recipients in an acute allograft rejection model, its influence on chronic allograft nephropathy is still unknown. In the present study, we assessed the influence of donor vagus nerve stimulation on survival, renal function and histology in a chronic allograft model. METHODS: Brain death was induced in Fisher rats, and electro-stimulation of the vagus nerve was applied in one group (BD + vagus) during the whole course of BD (6 h). Unstimulated BD Fisher donor rats served as controls. Allogeneic Lewis rats were used as recipients and no immunosuppressive medication was administered. Blood and urine samples were collected every second week. Banff classification was assessed from harvested allografts. RESULTS: Vagal stimulation of BD donors resulted in an improved survival of recipients. Long-term renal function was significantly better in these recipients as reflected by improved creatinine clearance. Banff classification revealed significantly reduced vasculopathy and less tubulopathy in the BD + vagus group. CONCLUSIONS: In conclusion, our data demonstrate a long-lasting beneficial effect of vagus nerve stimulation in BD donors on the renal transplantation outcome. Hence, activation of the cholinergic anti-inflammatory pathway in BD donors may represent a novel therapeutic modality to reduce chronic allograft nephropathy without any side effects for the recipient.
Assuntos
Glomerulonefrite/prevenção & controle , Rejeição de Enxerto/prevenção & controle , Nervo Vago/fisiopatologia , Aloenxertos/patologia , Aloenxertos/fisiopatologia , Animais , Morte Encefálica/fisiopatologia , Estimulação Elétrica , Terapia por Estimulação Elétrica , Rim/patologia , Rim/fisiopatologia , Transplante de Rim , Masculino , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Doadores de Tecidos , Transplante HomólogoRESUMO
OBJECTIVES: Thalidomide has various effects, such as immune modulation, anti-angiogenicity, anti-inflammation and anti-proliferation. Moreover, thalidomide modulates the activity of NF-κB, which can up-regulate the expression of downstream genes involved in the pathophysiology of LN. Here we investigated the efficacy of thalidomide monotherapy or thalidomide plus prednisolone (PL) on nephritis in NZB/WF1 mice at different doses and compared both with a combination therapy of MMF plus PL. METHODS: Forty-three female NZB/WF1 mice were divided into eight groups (untreated; 1.7, 5 or 10 mg/kg of thalidomide alone; 1.7, 5 or 10 mg/kg of thalidomide plus 1.5 mg/kg of PL and 33.3 mg/kg of MMF plus PL). Proteinuria and histological damage were evaluated. Immune complex deposition and nuclear translocation of NF-κB in kidney tissues were assessed by immunofluorescence staining. Serum concentrations of anti-dsDNA and IgG subclasses were also measured. RESULTS: In comparison with untreated mice, mice treated with 10 mg/kg of thalidomide monotherapy showed a significant decrease in proteinuria and significantly lower glomerular and tubular damage scores, comparable to 5 or 10 mg/kg of thalidomide plus PL or MMF plus PL. Also, treatment with 10 mg/kg of thalidomide significantly decreased immune complex accumulation, reduced the serum concentration of anti-dsDNA, IgG2a and IgG2b and inhibited nuclear translocation of NF-κB in kidney tissues, comparable to standard therapy for LN. CONCLUSION: These data suggest that thalidomide might play an anti-inflammatory role in the pathophysiology of LN, and it could serve as a complementary therapy to standard induction regimens for refractory LN.
Assuntos
Anti-Inflamatórios/farmacologia , Nefrite Lúpica/prevenção & controle , Talidomida/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/toxicidade , Complexo Antígeno-Anticorpo/metabolismo , DNA/metabolismo , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Imunoglobulina G/metabolismo , Imunossupressores/farmacologia , Nefrite Lúpica/sangue , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos NZB , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacologia , Prednisolona/administração & dosagem , Prednisolona/farmacologia , Proteinúria/prevenção & controle , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/toxicidadeRESUMO
OBJECTIVE: To determine whether inhibition of p38 mitogen-activated protein kinase (p38MAPK) reduces the pathogenicity of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in vitro and in vivo. METHODS: The effects of the p38MAPK-specific inhibitor AR-447 were studied in vitro using neutrophil respiratory burst and degranulation assays, and in lipopolysaccharide (LPS)-stimulated human glomerular endothelial cells. In vivo, p38MAPK inhibition was investigated in a mouse anti-myeloperoxidase (MPO) IgG/LPS glomerulonephritis model. Mice were treated orally with AR-447 daily, starting before (pretreatment group) or 24 h after disease onset (treatment group), and killed after 1 or 7 day(s). RESULTS: In vitro, AR-447 diminished neutrophil respiratory burst and degranulation induced by patient-derived MPO-ANCA and proteinase 3 (Pr3)-ANCA. In glomerular endothelial cells, AR-447 reduced LPS-induced secretion of IL-6 and IL-8, but not of MCP-1. In mice, pretreatment with AR-447 reduced albuminuria 1 day after induction of glomerulonephritis. After 7 days, no effects on urinary abnormalities were observed upon AR-447 pretreatment or treatment. Also, glomerular neutrophil accumulation was not diminished. In contrast, glomerular macrophage accumulation and the formation of glomerular crescents was significantly reduced by AR-447 pretreatment (vehicle: 12.5 ± 5.6% crescentic glomeruli; AR-447: 7.7 ± 2.7%) and treatment (vehicle 14.6 ± 1.8%; AR-447 6.0 ± 3.4%) at 7 days. CONCLUSION: This study shows that p38MAPK inhibition markedly reduces ANCA-induced neutrophil activation in vitro. In vivo, p38MAPK inhibition partly reduced crescent formation when the drug was administered prior to disease induction and after disease onset, suggesting that besides p38MAPK activity other signalling pathways contribute to the disease activity.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/prevenção & controle , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/enzimologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Células Cultivadas , Citocinas/biossíntese , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Glomerulonefrite/enzimologia , Glomerulonefrite/imunologia , Glomerulonefrite/prevenção & controle , Humanos , Imunoglobulina G/imunologia , Glomérulos Renais/imunologia , Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Knockout , Ativação de Neutrófilo/imunologia , Peroxidase/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Explosão Respiratória/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
AIM: Renal expression of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) contribute to the development of tubulointerstitial fibrosis characteristic of progressive forms of primary glomerulonephritis (GN). The aim of this study was to investigate the therapeutic effect of MMP inhibitor, doxycycline, administration in an experimental rat model of immune-complex nephritis (ICN). METHODS: The induction of immune-complex glomerulonephritis was carried out by the administration of an i.v. dose of 2 mg bovine serum albumin (BSA) daily for 28 days after 8 weeks of s.c. immunization with 1 mg of BSA in complete Freund's adjuvant. Doxycycline (30 mg/kg) was given daily (in groups 2 and 4) by gavage for 28 days. RESULTS: Animals treated with doxycycline showed significant reduction in glomerular area and cell proliferation than non-treated controls. Glomerular deposition of immunoglobulin (Ig)G and C3 was less intense in treated rats than non-treated controls. Although not statistically significant, interstitial inflammation was less intense in treated rats than non-treated controls. Glomerular expression of MMP-9 by immunoflourescence was significantly inhibited in the treated group. In addition pro-MMP-2 on gelatin zymography was importantly suppressed by doxycycline in ICN. CONCLUSION: Doxycycline, in addition to its antibiotic property, may, following further investigation, provide a possible survival benefit in proliferative glomerulonephritis.
Assuntos
Proliferação de Células/efeitos dos fármacos , Doxiciclina/farmacologia , Glomerulonefrite/prevenção & controle , Doenças do Complexo Imune/prevenção & controle , Glomérulos Renais/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Animais , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Adjuvante de Freund , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/enzimologia , Glomerulonefrite/patologia , Doenças do Complexo Imune/induzido quimicamente , Doenças do Complexo Imune/enzimologia , Doenças do Complexo Imune/patologia , Imuno-Histoquímica , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz/metabolismo , Ratos , Ratos Wistar , Soroalbumina Bovina , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismoRESUMO
The pathomechanisms of glomerulosclerosis in diabetic nephropathy (DN) are considered to be related with glycometabolism disorder, podocyte injury, intra-renal hemodynamics abnormality, fibrogenic cytokines over-expression, oxidative stress and inflammatory reaction. Chinese herbal medicine could delay the progression of glomerulosclerosis in DN by ameliorating the harmful factors of these pathological changes. Therefore, it is possible to postpone the progress of DN to end-stage renal disease through the treatment with Chinese herbal medicine.
Assuntos
Nefropatias Diabéticas/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Glomerulonefrite/prevenção & controle , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/metabolismo , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Glomerulonefrite/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.
Assuntos
Anticorpos Antinucleares/biossíntese , Aquicultura , Doenças Autoimunes/imunologia , Doenças Autoimunes/prevenção & controle , Vacinas Bacterianas/imunologia , Salmo salar/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Animais , Anticorpos Antinucleares/sangue , Aquicultura/métodos , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/efeitos adversos , Glomerulonefrite/imunologia , Glomerulonefrite/prevenção & controle , Humanos , Doenças do Complexo Imune/imunologia , Doenças do Complexo Imune/prevenção & controle , Imunoglobulina M/biossíntese , Imunoglobulina M/sangue , Células K562 , Hepatopatias/imunologia , Hepatopatias/prevenção & controle , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/prevenção & controle , Camundongos , Óleo Mineral/administração & dosagem , Óleo Mineral/efeitos adversos , Distribuição Aleatória , Trombose Venosa/imunologia , Trombose Venosa/prevenção & controle , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversosRESUMO
OBJECTIVE: To observe the effect of yishen capsule (YSC) on preventing the recurrence of chronic glomerulonephritis (CGN) and to explore its mechanism preliminarily. METHODS: CGN patients were assigned to the treated group (61 cases) and the control group (48 cases) and all of them were orally administered with 4 mg of Perindopril twice a day, but 3 capsules of YSC, thrice a day, were given additionally to patients in the treated group. The therapeutic course for both groups was 18 months. The recurrence rate of CGN at the 6th, 12th, and 18th month in the two groups was observed and compared, and the changes of 24-h urinary protein quantity and T-lymphocyte subsets before and after treatment were observed as well. RESULTS: (1) Comparison of recurrence rate between the two groups showed insignificant difference at the 6th month, but it did show significant difference at the 12th and the 18th month, which was significantly decreased in the treated group than in the control group (P<0.05, P<0.01); (2) The 24-h urinary protein quantity at the 18th month decreased significantly in both groups (P<0.05, P<0.01), but in the treated group was more significant (P<0.01); (3) T-lymphocyte subsets showed no obvious change in the control group after treatment (P>0.05), while in the treated group, it showed significant increase in CD3, CD4 and CD4/CD8 (P<0.05 or P<0.01) and significant decrease in CD8 (P<0.05), and also the difference after treatment in T-lymphocyte subsets between the two groups was significant (P<0.05 or P<0.01). CONCLUSION: YSC has marked effects in reducing the recurrence of CGN and in decreasing urinary protein, and its mechanism might be related with its function in regulating the ratio of T-lymphocyte subsets to enhance the immunity of patients.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/prevenção & controle , Adolescente , Adulto , Cápsulas , Estudos de Casos e Controles , Doença Crônica/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/efeitos dos fármacos , Masculino , Pacientes Desistentes do Tratamento , Proteinúria , Prevenção Secundária , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacosRESUMO
The anti-Thy1.1 glomerulonephritis (GN) model induced by anti-Thy1.1 monoclonal antibody (mAb) is a widely used animal model for human mesangial proliferative glomerulonephritis (MsPGN), which is characterized by significant proteinuria and acute or progressive mesangial injury following the complement-mediated mesangiolysis and glomerular inflammatory cell infiltration. In this review, it has been discussed that the pathogenesis of reversible anti-Thy1.1 GN or irreversible anti-Thy1.1 GN induced by mAb 1-22-3 injection, the mechanisms governing inflammatory cells infiltration and several injurious cytokines in glomeruli, and some of the processes involved in the resolution of mesangial lesion such as mesangial cell proliferation and matrix expansion. Using these models, it has been reported to examine the effects of Chinese materia medica, including multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) and Sairei-to on mesangial damage and proteinuria, and then to clarify the mechanism of these herbs at molecular level by examining the effects on various injurious factors.
Assuntos
Anticorpos Monoclonais/imunologia , Modelos Animais de Doenças , Glomerulonefrite/imunologia , Antígenos Thy-1/imunologia , Animais , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Glomerulonefrite/metabolismo , Glomerulonefrite/prevenção & controle , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Humanos , Tripterygium/químicaRESUMO
Astragalus membranaceus (AM) has been widely used for treating kidney diseases in traditional Chinese medicine. In this study, the Astragalus polysaccharide (APS), the main active ingredient was isolated and purified from the Rhizomes of AM, which consisted of d-glucopyranose and had the molecular weight of 3.6x10(4) Da. The effect of APS on glomerulonephritis rats induced by cationic Bovine Serum Albumin(C-BSA) was evaluated by flow cytometry using Nuclear Transcription Factor-kappaB (NF-kappaB) as marker. Interleukin-2 (IL-2), Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha) were determined by the ELISA method. The rats (model group and treatment group) were injected subcutaneously with C-BSA plus incomplete Freund's adjuvant on day 0, C-BSA was injected through the caudal vein from week 2 to week 7 to induce glomerulonephritis. The rats (treatment group) were given APS by intraperitoneal injection from week 2 to week 7. The expression of NF-kappaB and the concentration of IL-2, IL-6 and TNF-alpha were significantly decreased in the treatment group. This study clearly suggests that APS is effective in protecting against glomerulonephritis induced by C-BSA through the inhibition of NF-kappaB mediated-cytokine pathway.
Assuntos
Astragalus propinquus/química , Glomerulonefrite/prevenção & controle , NF-kappa B/metabolismo , Polissacarídeos/farmacologia , Animais , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Interleucina-2/sangue , Interleucina-6/sangue , Rim/metabolismo , Rim/patologia , Masculino , Polissacarídeos/isolamento & purificação , Proteinúria , Ratos , Ratos Wistar , Soroalbumina Bovina , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: To evaluate the effect of HSGJ on chronic allograft nephropathy (CAN) using standard rat model of CAN. METHOD: Renal transplantation was performed with Fisher rats as donors and Lewis rats as recipients. All the recipients were randomly divided into control group and medication groups (high and low dosage of HSGJ, fed every other day). After 16 weeks of treatment, renal function and the histological alteration of CAN were measured. The expression of the TGFbeta1 mRNA in the allograft was evaluated by real-time PCR. RESULT: The content of 24 h urine protein and the level of serum creatinine in the medication groups were significantly decreased (P < 0.01) as compared with control group, whereas the creatinine clearance was increased (P < 0.01). The degree of glomerular sclerosis and the Banff score of medication groups were lower than the control group respectively (P < 0.01), in consistent with decreased expression of the TGF 1mRNA. CONCLUSION: HSGJ can prevent the chronic allograft nephropathy and the mechanism may be related with its influence on the expression of the TGFbeta1.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Glomerulonefrite/prevenção & controle , Rejeição de Enxerto/tratamento farmacológico , Transplante de Rim/efeitos adversos , Animais , Doença Crônica , Glomerulonefrite/etiologia , Glomerulonefrite/imunologia , Imunossupressores/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Transplante HomólogoRESUMO
Leucocytes infiltrate into renal tissue and are involved in the pathogenesis of crescentic glomerulonephritis. The initial event in the process of leucocyte infiltration is characterized by selectin-mediated leucocyte rolling on endothelial surface. Role of selectins in pathogenesis of glomerulonephritis has still been controversial. Sulphated glycolipids and sulphated polysaccharides interfere with the binding of P- and L-selectin with carbohydrate ligands on endothelial cells or on leucocytes. Here we evaluated the role of selectins and the preventive effects of sulphated colominic acid (SCA), a synthetic sulphated polysaccharide, on experimental crescentic glomerulonephritis in Wistar-Kyoto (WKY) rats. Crescentic glomerulonephritis was induced by injection of nephrotoxic serum (NTS) in WKY rats. Rats subsequently received intraperitoneal injection of saline, neutralizing or non-neutralizing monoclonal antibody (mAb) to rat P-selectin and L-selectin, SCA (5 or 10mg/kg/day) or nonsulphated colominic acid (CA) (10mg/kg/day) for 2 weeks. Localization of P-, E-selectin, ligands for L-selectin and intraglomerular leucocytes was examined by immunohistochemistry. Gene expression of platelet-derived growth factor (PDGF) B chain in glomeruli was quantified using real-time RT-PCR. P-selectin was highly expressed on glomerular endothelial cells after injection of NTS, whereas E-selectin and L-selectin ligands were not detected. Anti-P-selectin mAb, but not anti-L-selectin mAb, significantly reduced glomerular infiltration of macrophages, crescent formation, and proteinuria. SCA also reduced proteinuria, macrophage infiltration, and crescent formation in a dose-dependent manner. Furthermore, SCA suppressed gene expression of PDGF B chain in glomeruli. Our results indicate that P-selectin partially mediates glomerular infiltration of macrophage in experimental crescentic glomerulonephritis. Moreover, SCA may inhibit intraglomerular infiltration of macrophages by interfering with P-selectin-dependent adhesion pathway, and progression of experimental crescentic glomerulonephritis.
Assuntos
Glomerulonefrite/prevenção & controle , Macrófagos/efeitos dos fármacos , Selectina-P/fisiologia , Polissacarídeos/uso terapêutico , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Adesão Celular/efeitos dos fármacos , Quimiotaxia de Leucócito , Avaliação Pré-Clínica de Medicamentos , Selectina E/imunologia , Selectina E/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Imunoglobulina G/toxicidade , Molécula 1 de Adesão Intercelular/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Selectina L/imunologia , Selectina L/fisiologia , Macrófagos/fisiologia , Camundongos , Estrutura Molecular , Selectina-P/biossíntese , Selectina-P/genética , Selectina-P/imunologia , Reação em Cadeia da Polimerase , Polissacarídeos/farmacologia , Ligação Proteica/efeitos dos fármacos , Proteinúria/etiologia , Proteinúria/prevenção & controle , Proteínas Proto-Oncogênicas c-sis/biossíntese , Proteínas Proto-Oncogênicas c-sis/genética , Ratos , Ratos Endogâmicos WKYRESUMO
Previous studies have shown that reduction of renal mass in the rat remnant kidney model induces overproduction of transforming growth factor beta1 (TGFbeta1). We investigated whether an antioxidant, vitamin E, administered before the renal mass reduction, could prevent oxidative stress, reduce the overproduction of TGFbeta1, and mitigate against the subsequent glomerulosclerosis. Our results revealed that the oxidative stress, as measured by the change in plasma malondialdehyde, is significantly reduced by prior vitamin E dietary supplementation. Finally, our data show that dietary vitamin E supplementation ameliorates the rise in TGFbeta1 secondary to renal mass reduction and inhibits the glomerular sclerosis of the remnant kidney over the time course of this experiment.
Assuntos
Glomerulonefrite/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Vitamina E/farmacologia , Animais , Creatinina/sangue , Alimentos Fortificados , Glomerulonefrite/patologia , Córtex Renal/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Nefrectomia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/metabolismo , Vitamina E/sangueRESUMO
The effect of mycophenolate mofetil (MMF) was examined in active Heymann nephritis (HN), an animal model of human membranous nephropathy. HN was induced in Lewis rats with Fx1A/complete Freund's adjuvant (CFA), and controls only received CFA. The induction of HN was prevented by MMF (30 mg/kg per d) from 0 to 4 wk after immunization. Proteinuria was not different in CFA controls up to 16 wk, and was significantly less than in untreated HN from 6 wk onward. Serum anti-Fx1A antibody (Ab) levels and glomerular Ig deposition were suppressed during therapy. The interstitial infiltrate of alphabetaTCR+, CD4+ and CD8+ T cells, natural killer cells, and macrophages (mphi) observed in untreated HN at 8 wk was absent from rats treated from 0 to 4 wk with MMF. Semiquantitative reverse transcription-PCR for renal mononuclear cell cytokine mRNA at 8 wk demonstrated that MMF from 0 to 4 wk prevented the increased expression of Th1 (interferon-gamma, lymphotoxin), Th2 (interleukin-4), and mphi (tumor necrosis factor-alpha) cytokines identified in untreated HN. In lymph node draining sites of immunization, MMF limited both enlargement and the increased proportion of CD3+, CD4+, and CD8+ T cells observed in untreated HN and CFA controls. MMF suppressed Th2 (interleukin-4) but not Th1 (interferon-gamma, lymphotoxin) cytokine mRNA expression in lymph nodes. MMF from 4 to 8, 6 to 12, or 10 to 14 wk did not prevent proteinuria, serum anti-Fx1A Ab, or glomerular IgG deposition when compared with untreated HN. This study showed that MMF from 0 to 4 wk prevented the induction of HN and was associated with preferential suppression of Th2 cytokines. This therapy may prove useful in human idiopathic membranous nephropathy.
Assuntos
Glomerulonefrite/prevenção & controle , Linfocinas/metabolismo , Ácido Micofenólico/análogos & derivados , Células Th2/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/prevenção & controle , Humanos , Interferon gama/biossíntese , Interferon gama/genética , Interleucinas/biossíntese , Interleucinas/genética , Interleucinas/metabolismo , Córtex Renal/imunologia , Córtex Renal/patologia , Linfocinas/biossíntese , Linfocinas/genética , Masculino , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Proteinúria/etiologia , Proteinúria/prevenção & controle , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos Lew , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The effects of traditional Chinese medicine (Sairei-to) on experimental glomerulonephritis induced in rats by monoclonal antibody (mAb) 1-22-3 injection was examined. The level of proteinuria in the Sairei-to-treated group was significantly lower than that in the PBS treated group. This suppressive effect was caused by the major component of Sairei-to, Syo-saiko-to but not by another component, Gorel-san. The suppressive effect of Syo-saiko-to was identified in its components (Bupleuri radix, Pinelliae tuber and Zingiberis rhizoma), but not in the other combined components (Ginseng radix and Zizyphi fructus). Further study revealed that the suppressive effects of the combined components were mainly derived from Bupleuri radix. It was demonstrated that the actual active ingredient is probably Saikosaponin-d. Light microscopy revealed that Sairei-to and its effective components suppressed the proliferation of mesangial cells and mesangial matrix expansion. Semiquantitative morphological studies of glomerular lesions on the eighth day showed that Syo-saiko-to and its combined components (Bupleuri radix, Zingiberis rhizoma and Pinelliae tuber) suppressed mesangial matrix expansion significantly compared with phosphate-buffered saline control groups (matrix score: 28.0 +/- 19.1 vs 102.3 +/- 14.1; 30.9 +/- 30.1 vs 102.3 +/- 14.1, P < 0.005, respectively). It was concluded that Saikosaponin-d, as well as Bupleuri radix, Syo-saiko-to and Sairei-to can suppress proteinuria and morphological changes in the rat glomerulonephritis model induced by mAb 1-22-3.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Glomerulonefrite/prevenção & controle , Rim/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Proteinúria/prevenção & controle , Saponinas , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anticorpos Monoclonais , Análise Química do Sangue , Feminino , Glomerulonefrite/etiologia , Rim/patologia , Ratos , Ratos Wistar , Sapogeninas/administração & dosagemRESUMO
To clarify whether angiotensin converting enzyme (ACE) inhibitors prevent progressive renal injury directly by their antihypertensive effect we administered the ACE inhibitor lisinopril to male MWF/Ztm rats as a single daily dose that lowered blood pressure for only 9 of 24 h. We investigated the effects of this treatment in short- and long-term studies and compared them with another antihypertensive drug, the calcium channel blocker nitrendipine, given to partially control blood pressure as done with the ACE inhibitor. In untreated animals systemic hypertension, proteinuria, and glomerulosclerosis developed spontaneously with age, and lisinopril reduced systemic hypertension and prevented proteinuria and glomerular lesions. Nitrendipine, despite similar blood pressure control, was ineffective in preventing both proteinuria and glomerulosclerosis. After 2 mo of treatment glomerular capillary pressure was significantly reduced by lisinopril and slightly but significantly increased by nitrendipine, compared with untreated controls. The ultrafiltration coefficient was significantly higher in lisinopril than in controls and not significantly changed by nitrendipine. With both drugs, however, glomerular hemodynamic effects were observed only at a few hours after administration and were abolished before the next administration. No significant changes in glomerular tuft volume were observed in treated and untreated animals after 2 and 6 mo of observation. Thus ACE inhibitor, despite only partial control of systemic blood pressure, effectively prevented proteinuria and glomerular injury. Comparable blood pressure control obtained with a calcium channel blocker was not associated with renal protection. These results suggest that ACE inhibitors could protect glomerular microcirculation by a mechanism that is not directly related to their antihypertensive action.