RESUMO
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
BACKGROUND: IgA nephropathy (IgAN) is the most common glomerular disease worldwide. It has a high incidence in Asians and is more likely to progress to end-stage renal disease (ESRD). For high-risk IgAN, which is clinically characterized by massive proteinuria and renal dysfunction, however, there has been no international consensus on treatment options. Compared with other developed countries, IgAN patients in China are often found to have severe kidney function loss at initial diagnosis. Yi-Qi-Qing-Jie formula (YQF; a compound recipe of Chinese medicinal herbs) has shown potential renal protection in our previous clinical studies. To further confirm the efficacy and safety of YQF in the treatment of high-risk IgAN, we have designed a prospective double-blind randomized placebo-controlled trial. METHODS/DESIGN: The TCM-WINE study is a single-center, prospective, double-blind randomized placebo-controlled trial. We plan to randomize 60 participants with biopsy-proven IgAN to a YQF combined group (YQF compound combined with prednisolone, and cyclophosphamide if necessary) or an immunosuppression group (placebo-YQF combined with prednisolone, and cyclophosphamide if necessary). The two groups will enter a 48-week in-trial treatment phase and receive post-trial follow-up until study completion (3 years). All patients will receive optimal supportive care. The primary composite outcome is defined as the first occurrence of a 40% decrease in estimated glomerular filtration rate (eGFR) from the baseline lasting for 3 months, initiating continuous renal replacement treatment, or death due to chronic kidney disease (CKD) during the 3-year study phase. The secondary endpoint events are defined as the mean annual eGFR decline rate (eGFR slope, ml/min per 1.73 m2 per year), which is calculated by the eGFR regression curve for each eligible patient, and proteinuria remission (prescribed as proteinuria < 0.5 g/day) at weeks 24, 36, and 48 during the in-trial phase. The remission rate of symptoms and inflammation status will be evaluated at week 48. Safety monitoring and assessment will be undertaken during the study. DISCUSSION: The TCM-WINE study will evaluate the effects and safety of YQF combined therapy compared with immunosuppression monotherapy on the basis of the optimal supportive treatment in high-risk IgAN. The evidence from this study will provide a novel, effective, and safe Chinese characteristic therapy for high-risk IgAN patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03418779. Registered on 18 June 2018.
Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Glomerulonefrite por IGA/tratamento farmacológico , Imunossupressores/administração & dosagem , Falência Renal Crônica/epidemiologia , Adolescente , Adulto , Idoso , China/epidemiologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/mortalidade , Glomerulonefrite por IGA/patologia , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/imunologia , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Terapia de Substituição Renal/estatística & dados numéricos , Resultado do Tratamento , Adulto JovemRESUMO
An eight-year-old girl, presenting with palpebral edema, gross hematuria, and foam in urine, was admitted to our hospital. Investigations indicated increased serum antistreptolysin O (ASO) and anti-mycoplasma antibody titers. Renal biopsy showed crescentic poststreptococcal acute glomerulonephritis (CPAGN) with isolated C3 deposition in the glomeruli. Electro-microscope examination showed subepithelial deposition of electron dense material. She received the double pulse therapies of methylprednisolone and cyclophosphamide as well as the treatment of oral prednisolone, angiotensin converting enzyme-II (ACE-II) inhibitor, dipyridamole and traditional Chinese medicine. The complete clinical remission was achieved after 9 months. No serious adverse effects were observed during the follow-up. Our findings indicated that CPAGN with isolated C3 deposition might have a favorable prognosis after aggressive immunosuppressive treatment. However, the influence of isolated C3 deposition on CPAGN prognosis remains to be clarified.
Assuntos
Complemento C3/análise , Glomerulonefrite/imunologia , Glomérulos Renais/imunologia , Infecções Estreptocócicas/imunologia , Doença Aguda , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Biomarcadores/análise , Biópsia , Criança , Quimioterapia Combinada , Feminino , Imunofluorescência , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/ultraestrutura , Microscopia Eletrônica , Indução de Remissão , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/diagnóstico , Fatores de Tempo , Resultado do TratamentoRESUMO
Increasing evidence suggests the heterogeneity of macrophage phenotype and function ultimately determines the outcome of diabetic nephropathy (DN). This study aimed to investigate the effects of vitamin D on macrophage M1/M2 phenotype and its role in preventing podocyte impairment in streptozotocin-induced DN rats. Calcitriol, a bioactive 1,25-dihydroxyvitamin D3, ameliorated proteinuria and renal damage as well as reversed the decline of both nephrin and podocin, crucial structural proteins in podocytes. DN rats showed increased infiltrating macrophages with M1 phenotype characterized by elevated expression of inducible nitric oxide synthase and TNF-α in glomeruli and interstitium, which were inhibited after calcitriol treatment. Interestingly, calcitriol promoted M2 macrophage activation with enhanced expression of CD163, arginase-1, and mannose receptor at week 18 but not at week 8 or 14. The ratio of CD163 to CD68, considered as the proportion of M2 macrophages, was about 2.9-fold higher at week 18 after calcitriol treatment. Furthermore, the protein expression of inducible nitric oxide synthase, a crucial marker of M1 macrophages, was negatively correlated with the expression of either nephrin or podocin, whereas CD163, indicating M2 macrophages, was positively correlated. In vitro, 1,25-dihydroxyvitamin D3 switched high-glucose-induced M1 macrophages toward an M2 phenotype in either U937-derived macrophages or RAW264.7 cells. Our results suggest that vitamin D not only reduces macrophage infiltration and inhibits M1 macrophage activation but also enhances M2 macrophage phenotype to protect against podocyte injury.
Assuntos
Calcitriol/uso terapêutico , Nefropatias Diabéticas/prevenção & controle , Macrófagos/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Vitaminas/uso terapêutico , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Calcitriol/farmacologia , Avaliação Pré-Clínica de Medicamentos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Testes de Função Renal , Glomérulos Renais/imunologia , Masculino , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Podócitos/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/metabolismo , Vitaminas/farmacologiaRESUMO
Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide exhibiting anti-inflammatory activity in experimental models of autoimmune diseases. However, no studies thus far have examined the effects of α-MSH on systemic lupus erythematosus (SLE). This study aimed to determine the effects of an α-MSH agonist in induced murine lupus. Here we employed female Balb/cAn mice in which lupus was induced by pristane. Groups of lupus animals were treated daily with the α-MSH analogue [Nle4, DPhe7]-α-MSH (NDP-MSH) (1·25 mg/kg) injected intraperitoneally or saline for 180 days. Normal animals comprised the control group. Arthritis incidence, plasma immunoglobulin (Ig)G isotypes, anti-nuclear antibodies (ANA) and plasma cytokines were evaluated. Renal function was assessed by proteinuria and histopathological lesion. Glomerular levels of IgG, α-smooth muscle actin (α-SMA), inducible nitric oxide synthase (iNOS), C3, CD3, melanocortin receptors (MCR)1, corticotrophin-releasing factor (CRF) and α-MSH was estimated by immunohistochemistry. When compared with normal controls, lupus animals exhibited increased arthritis, IgG levels, ANA, interleukin (IL)-6, IL-10, proteinuria and mesangial cell proliferation together with glomerular expression of α-SMA and iNOS. Glomerular expression of MCR1 was reduced in lupus animals. NDP-MSH treatment reduced arthritis scores by 70% and also diminished IgG1 and IgG2a levels and ANA incidence. In the glomerulus, NDP-MSH treatment reduced cellularity by 50% together with reducing IgG deposits, and expression levels of α-SMA, iNOS and CRF were also all decreased. Taken together, our results suggest for the first time that α-MSH treatment improves several parameters of SLE disease activity in mice, and indicate that this hormone is an interesting potential future treatment option.
Assuntos
Lúpus Eritematoso Sistêmico/metabolismo , alfa-MSH/metabolismo , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Artrite/tratamento farmacológico , Artrite/etiologia , Artrite/imunologia , Artrite/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Receptor Tipo 1 de Melanocortina/metabolismo , Terpenos/efeitos adversos , alfa-MSH/administração & dosagemRESUMO
Curcumin has been used in Asian traditional medicine for its medicinal properties. Recent studies have demonstrated that curcumin has antioxidant, anti-tumour and anti-inflammatory activities. The aim of the present study is to investigate the effects of curcumin on established lupus nephritis (LN) in New Zealand Black/White (NZB/W) F1 female mice, in particular, its interaction with regulatory T (Treg) cells. Starting at 18 weeks of age, mice were fed a standard diet or a diet containing 1 % curcumin until the end of the study. The proteinuria level and the serum levels of IgG1, IgG2a and anti-double-stranded DNA (dsDNA) IgG antibodies were measured. Additionally, IgG immune complex deposition in the glomeruli and renal inflammation were compared between curcumin-treated mice and control mice. Curcumin decreased the proteinuria level and serum levels of IgG1, IgG2a and anti-dsDNA IgG antibodies in NZB/W F1 female mice. IgG immune complex deposition in the glomeruli was reduced in curcumin-treated mice. Furthermore, renal inflammation was also decreased after curcumin treatment. Interestingly, these therapeutic effects of curcumin disappeared after Treg depletion by anti-CD25 antibody injection. Curcumin exerted a protective effect against LN in NZB/W F1 mice. We speculate that the protective effects of curcumin in LN may involve, at least in part, its interaction with Treg cells.
Assuntos
Curcuma/química , Curcumina/uso terapêutico , Imunoglobulina G/metabolismo , Glomérulos Renais/efeitos dos fármacos , Nefrite Lúpica/prevenção & controle , Fitoterapia , Linfócitos T Reguladores/metabolismo , Animais , Anticorpos , Anticorpos Antinucleares/metabolismo , Complexo Antígeno-Anticorpo/metabolismo , Curcumina/farmacologia , Suplementos Nutricionais , Feminino , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteinúria/prevenção & controleRESUMO
Multi-glycoside, one of the extracted compounds from Tripterygium wilfordii HOOK. f. (GTW), has been shown to be clinically effective in suppressing glomerular inflammation in chronic kidney disease. However, its clinical application is often limited by its cytotoxic actions on the liver. This study was performed to contrast the dose-effects of GTW on glomerular inflammation and hepatic damage in two types of anti-Thy1.1 glomerulonephritis (GN). Rats with acute or chronic anti-Thy1.1 GN were either left untreated (the Vehicle group) or treated with a high or low dose of GTW and sacrificed on day 7 or day 45. GTW was administrated 3 days before or at the same time as the antibody injection and lasted until sacrifice. GTW at high dose ameliorated glomerular macrophage accumulation, mesangial proliferation, proteinuria, and interleukin-2 expression in the acute anti-Thy1.1 GN model, but caused structural and functional lesions in the liver. In contrast, GTW at low dose improved activated macrophage and T lymphocyte infiltration, mesangial injury, proteinuria, and interleukin-2 and interferon-γ expressions without hepatic toxicity in the chronic model of GN induced by anti-Thy1.1 antibody. In conclusion, GTW at low dose not only effectively inhibits glomerular inflammation but also avoids severe injuries to the liver.
Assuntos
Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Glicosídeos/fisiologia , Mediadores da Inflamação/fisiologia , Isoanticorpos/toxicidade , Hepatopatias/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tripterygium , Animais , Relação Dose-Resposta Imunológica , Feminino , Glomerulonefrite/imunologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Hepatopatias/imunologia , Hepatopatias/patologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Ratos , Ratos Wistar , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologia , Tripterygium/imunologiaRESUMO
BACKGROUND: Growing evidence suggests that blockade of the aldosterone-receptor may preserve kidney function by anti-inflammatory effects independent of the blood pressure. We hypothesized that the selective aldosterone-receptor antagonist eplerenone has a profound anti-inflammatory effect in the autologous phase of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). METHODS: Mice received ≈200mg/kg body wt/day eplerenone via supplemented chow diet or standard chow starting at the day of immunization with rabbit IgG. Three days later the anti-GBM antibody was injected and the experiments were stopped at day 7 and 14. RESULTS: Mice receiving eplerenone showed significantly decreased albuminuria and glomerular sclerosis at day 7 and 14 after induction of anti-GBM GN. Eplerenone treatment significantly inhibited the infiltration of CD4+, CD8+ T cells and macrophages into the kidneys. Circulating levels and glomerular deposition of autologous IgG were comparable in both groups. At day 7 the pro-inflammatory cytokines MCP-1 and IL-6 were found to be significantly decreased in regional draining lymph nodes of eplerenone-treated mice, whereas the anti-inflammatory cytokine IL-10 was significantly upregulated. In line, splenocytes from eplerenone-treated nephritic mice produced significantly increased IL-10. CONCLUSION: Aldosterone-receptor blockade by eplerenone effectively attenuated proteinuria, kidney damage and the inflammatory response in anti-GBM GN by significantly decreasing pro-inflammatory cytokines in the regional draining lymph nodes of the kidney. Our results suggest that this selective aldosterone receptor antagonist is a possible additional tool in the treatment of GN.
Assuntos
Doença Antimembrana Basal Glomerular/prevenção & controle , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Espironolactona/análogos & derivados , Albuminúria , Animais , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citocinas/metabolismo , Eplerenona , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Masculino , Camundongos , Coelhos , Espironolactona/uso terapêutico , Baço/efeitos dos fármacos , Baço/metabolismoRESUMO
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
Hematopoietic growth factors (HGF) mobilize potential tolerogenic cells in transplant donors. Fms-like tyrosine kinase 3 ligand (Flt3L) mobilizes stem cells and dendritic cells (DCs) in human and nonhuman primate blood. Blood and renal and liver biopsies were obtained from untreated and Flt3L-mobilized rhesus macaques. Flt3L increased the number of myeloid CD11c(hi) and plasmacytoid CD123(hi) precursors in blood and both myeloid CD11c(+) HLA-DR(+) fascin(+) (CD45RA(-)) DCs and putative plasmacytoid CD11c(lo) CD45RA(hi) DC precursors in liver and kidneys, without affecting organ function. DC in Flt3L-treated monkeys were concentrated in the glomeruli and interstitium of kidneys, and in the portal triads and parenchyma of liver. These DCs exhibited the phenotype of immature antigen-presenting cells (APCs; CD83(-) CD86(lo) CCR5(+) CCR7(-)). HGF-induced changes reversed significantly within 7 days of Flt3L withdrawal. Therapeutic protocols that mobilize donor hematopoietic cells should consider the influence of HGF on the APC constituency of prospective organ allografts.
Assuntos
Células Dendríticas/imunologia , Substâncias de Crescimento/farmacologia , Transplante de Rim/imunologia , Transplante de Fígado/imunologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Terapia Biológica , Células Dendríticas/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Transplante de Rim/patologia , Transplante de Fígado/patologia , Macaca mulatta , Proteínas de Membrana/uso terapêutico , Modelos AnimaisRESUMO
Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Although treatment with corticosteroids and cytotoxic drugs may be useful in many cases, morbidity associated with these drugs and the relapsing nature of the disease make it necessary to develop new treatment strategies. Five-month old female NZB/W F1 mice were divided into the following groups: CYP group (n = 10), cyclophosphamide (CYP) 50 mg/kg intraperitoneally every 10 days; RAPA 1 group (n = 10) oral daily sirolimus (SRL), 1 mg/kg; RAPA 12 group (n = 13), oral daily SRL, 12mg/kg; FTY group (n = 10), oral fingolimod (FTY720), 2 mg/kg three times per week. An additional group of 13 non-treated mice were used as a control (control group). Follow-up was performed over four months. Animal survival, body weight, anti-DNA antibodies and proteinuria were determined. Kidneys were processed for conventional histology and immunofluorescence for IgG and complement. Total histological score (HS) was the sum of mesangial expansion, endocapillary proliferation glomerular deposits, extracapillary proliferation, interstitial infiltrates, tubular atrophy and interstitial fibrosis. All treated groups had lower proteinuria at the end of the follow-up with respect to the control group (P < 0.0001). Serum anti-DNA antibodies were appropriately controlled in RAPA 1 and CYP groups, but not in FTY or RAPA 12 groups. SRL and CYP arrested, and perhaps reversed almost all histological lesions. FTY720 ameliorated histological lesions but did not control mesangial expansion or interstitial infiltrates. SRL produces great improvement in murine lupus nephritis, while FTY720 seems a promising alternative if used in appropriate doses.
Assuntos
Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Propilenoglicóis/uso terapêutico , Sirolimo/uso terapêutico , Esfingosina/análogos & derivados , Administração Oral , Animais , Anticorpos Antinucleares/sangue , Apoptose/imunologia , Autoantígenos/imunologia , Movimento Celular/efeitos dos fármacos , Cromatina/imunologia , Complemento C3/análise , Fator Nefrítico do Complemento 3/análise , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Cloridrato de Fingolimode , Mesângio Glomerular/patologia , Imunoglobulina G/análise , Imunossupressores/farmacologia , Injeções Intraperitoneais , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos NZB , Nucleossomos/imunologia , Propilenoglicóis/administração & dosagem , Propilenoglicóis/farmacologia , Proteinúria/etiologia , Receptores de Lisoesfingolipídeo/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Esfingosina/administração & dosagem , Esfingosina/farmacologia , Esfingosina/uso terapêuticoRESUMO
The pharmacokinetics of panipenem in experimental renal failure animal models was investigated in order to identify the appropriate covariates affecting the pharmacokinetic behavior. Panipenem and betamipron were administered intravenously to rats with a variety of renal failures, such as nephritis induced by glycerol, gentamicin, uranium and antiserum against glomerular basement membrane as well as 5/6 subtotal nephrectomy. Panipenem in plasma and urine was determined and pharmacokinetic analysis was performed using a one-compartment open model. The elimination half-life prolonged and total body clearance, renal clearance (CL(R)) and renal excretion ratio were decreased according to the renal function, i.e. control>glycerol>anti-GBM=gentamicin>nephrectomy=uranium in order. However, distribution volume was consistent in all models. CL(R) showed strong positive correlation with the glomerular filtration rate in spite of a weak correlation with the reciprocal of blood urea nitrogen. However, no obvious correlation was observed with secretory clearance of N-1-methylnicotinamide. This preliminary information based on animal model might be useful for designing pharmacokinetic studies in special population at early stage of new drug development.
Assuntos
Insuficiência Renal/metabolismo , Tienamicinas/farmacocinética , Animais , Antibacterianos , Área Sob a Curva , Autoanticorpos , Membrana Basal/imunologia , Nitrogênio da Ureia Sanguínea , Cromatografia Líquida de Alta Pressão , Gentamicinas , Taxa de Filtração Glomerular , Glicerol , Meia-Vida , Testes de Função Renal , Glomérulos Renais/imunologia , Masculino , Nefrite/induzido quimicamente , Nefrite/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/fisiopatologia , Espectrofotometria Ultravioleta , Distribuição Tecidual , UrânioRESUMO
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, yet there is no effective or specific therapy. Shen San Fang (S3F) is a traditional Chinese herbal medicinal formula that has been used in China for many years to treat patients with hematuria. The aim of this study is to test the therapeutic value of S3F in an experimental model of IgAN. IgAN was induced in Lewis rats by continuous oral immunization with bovine gamma-globulin (BGG) in the drinking water for 8 weeks, followed by intravenous injection of 1 mg BGG daily for 3 successive days. The rats were randomly divided into four groups (five rats/group): control, control receiving S3F, induction of IgAN, and IgAN receiving S3E S3F decoction was fed to rats beginning week 4 from the first day of oral sensitization with BGG. The S3F treatment was continued until the rats were sacrificed or for a 4-week period. Hematuria, renal immunohistochemistry for IgA and transforming growth factor-beta 1 (TGF-beta1), renal histopathology, and renal content of TGF-beta1 were measured. Rats developing IgAN had marked hematuria, profound mesangial proliferation and mesangial expansion, intense and diffuse glomerular IgA deposition, increased glomerular TGF-beta1 expression, and raised renal TGF-beta1 levels. S3F treatment resulted in a significant reduction of hematuria, decreased mesangial IgA deposition, weaker immunostaining of TGF-beta1 in glomerulus, and a lower renal TGF-beta1 concentration. Our animal data suggests a therapeutic value for the Chinese medicinal formula S3F in experimental IgAN. This beneficial effect was due to reduced glomerular IgA deposition and TGF-beta1 expression. Our preliminary findings hold promise for future human therapy.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Glomerulonefrite por IGA/tratamento farmacológico , Animais , Modelos Animais de Doenças , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Hematúria/tratamento farmacológico , Imunização , Imuno-Histoquímica , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Ratos , Ratos Endogâmicos Lew , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1 , Urinálise , gama-Globulinas/imunologiaRESUMO
BACKGROUND: Retinoic acid (tRA) is an active metabolite of vitamin A with potent anti-inflammatory properties. We analyzed the effects of tRA on the development of lupus nephritis in MRL/lpr mice. METHODS: MRL/lpr mice received chow supplemented with vehicle or tRA (daily 10 mg/kg) from 8 to 14 weeks until their sacrifice. MRL/wt mice served as an additional control. RESULTS: tRA-treated MRL/lpr mice showed reduced lymphoadenopathy and splenomegaly as compared to vehicle-treated controls. Treatment reduced proteinuria to almost basal levels. Plasma IgG and anti-DNA antibodies increased comparably in both vehicle and tRA-treated mice. Vehicle-treated mice showed characteristic renal lesions. In contrast tRA-treated mice showed almost normal glomerular histology with a pronounced reduction in endocapillary cell proliferation. T-cell and macrophage infiltrates were reduced after tRA treatment within glomeruli and interstitium as compared to vehicle-treated animals. In spite of this, immune complex and complement deposition were comparable in both groups. Adoptively transferred T cells from vehicle-treated to tRA-treated MRL/lpr mice did not induce renal lesions or proteinuria. These beneficial effects of tRA treatment were associated with reduced renal expression of chemokines and inflammatory cytokines. Surprisingly, renal transforming growth factor-beta (TGF-beta) mRNA levels of tRA-treated mice were elevated, possibly indicating that TGF-beta acts as an anti-inflammatory signal in this lupus model. CONCLUSION: tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.
Assuntos
Antineoplásicos/farmacologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/prevenção & controle , Tretinoína/farmacologia , Transferência Adotiva , Animais , Peso Corporal , Quimiocinas/genética , Citocinas/genética , Imunoglobulina G/sangue , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos MRL lpr , Tamanho do Órgão , RNA Mensageiro/análise , Linfócitos T/citologiaRESUMO
It has been observed that with Masugi nephritis in Wistar rats the initiation of endocapillary proliferative changes with macrophage accumulation is usually followed by glomerular sclerosis without extracapillary extension. In the present study, the provocation of an extracapillary lesion was attempted using accelerated Masugi nephritis in Wistar-Kyoto rats. In order to accelerate the accumulation of monocyte/macrophages, the administration of methylcellulose was added in an additional group. The development and fate of extracapillary lesions were analyzed histopathologically and immunohistochemically. As a result, the formation of extracapillary proliferation of granulomatous lesions could be initiated in this model. Granulomatous lesions were composed of CD4+ T cells and CD8+ T cells and monocyte/macrophages including multinucleated giant cells. These inflammatory cells had seemingly escaped from the capillary lumen through the injured glomerular basement membrane and formed cellular and granulomatous crescents. In addition, tenascin was strongly expressed in cellular crescents and was a unique extracellular matrix at this cellular stage. The cellular crescents then progressed to sclerosis with the formation of increased collagenous extracellular matrix. These results suggest that a delayed-type hypersensitivity plays a role in granulomatous crescent formation, even though the initial glomerular injury was evoked by a humoral antibody.
Assuntos
Doença Antimembrana Basal Glomerular/patologia , Granuloma/patologia , Glomérulos Renais/patologia , Animais , Doença Antimembrana Basal Glomerular/imunologia , Doença Antimembrana Basal Glomerular/metabolismo , Doença Antimembrana Basal Glomerular/fisiopatologia , Membrana Basal/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Adjuvante de Freund , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Imuno-Histoquímica , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Macrófagos/patologia , Masculino , Metilcelulose/farmacologia , Fosfatos/metabolismo , Proteinúria/fisiopatologia , Coelhos , Ratos , Ratos Endogâmicos WKYRESUMO
Alpha-tocopherol and fish oil have been reported to modulate the progression of IgA nephropathy in animals and humans. Because fish oil has been reported to exacerbate renal disease in subtotal nephrectomized rats, we investigated the effects of fish oil, with and without alpha-tocopherol, on the course of IgA nephropathy. Experimental IgA nephropathy was induced in male Sprague-Dawley rats, weighing 170-200 g, by oral and i.v. immunization with bovine gamma-globulin for 8 wk. IgA nephropathy was evidenced by hematuria, proteinuria, and IgA deposition in the mesangium. Standard rodent chow, containing 30 IU of alpha-tocopherol/kg of diet, was given to the control and IgA nephropathy rats. Fish oil (20% wt/wt), stripped of alpha-tocopherol preservative, was given to control and a second group of IgA nephropathy rats. Alternatively, corn oil or fish oil was supplemented with alpha-tocopherol at 100 IU/kg of diet and given to the third and fourth groups of IgA nephropathy rats. All animals were killed at 8 wk. Urinary protein excretion, plasma and kidney alpha-tocopherol concentrations, as well as glomerular planar area, and kidney transforming growth factor-beta1 mRNA were analyzed. As determined by reductions in proteinuria, glomerular planar area, and TGF-beta1 mRNA, fish oil with alpha-tocopherol ameliorated the renal injury induced by bovine gamma-globulin, whereas fish oil without alpha-tocopherol did not. Our findings support the importance of alpha-tocopherol, more so than fish oil, in mitigating the injury and promoting repair in experimental IgA nephropathy.
Assuntos
Óleos de Peixe/farmacologia , Glomerulonefrite por IGA/prevenção & controle , Glomerulonefrite por IGA/fisiopatologia , Vitamina E/farmacologia , Animais , Bovinos , Gorduras na Dieta , Glomerulonefrite por IGA/patologia , Rim/patologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Masculino , Nefrectomia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Transcrição Gênica , Fator de Crescimento Transformador beta/biossíntese , gama-Globulinas/imunologiaRESUMO
We present here the complete primary structure of human gp330, the human variant of the principal kidney autoantigen causing Heymann membranous glomerulonephritis in rats. The deduced 4655 amino acid residues give a calculated molecular mass of 519636 Da for the mature protein and consists of a probable 25-amino-acid N-terminal signal peptide sequence, an extracellular region of 4398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acid residues. Three types of cysteine-rich repeats characteristic of the low density lipoprotein receptor (LDLR) superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising four distinct domains, 16 growth factor repeats separated by eight YWTD spacer regions, and one epidermal growth factor-like repeat. No consensus cleavage sequence for the processing endoprotease furin is detected in human gp330. The intracellular tail contains not only two copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, but also intriguing and potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330 with minor differences between the extracellular and intracellular regions. Recently gp330 has been implicated in Ca2+ regulation in the parathyroid, the placenta, and the renal tubule, but its overall physiological and pathological role still remains uncertain.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Glicoproteínas de Membrana/genética , Transdução de Sinais , Sequência de Aminoácidos , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Clonagem Molecular , DNA Complementar , Complexo Antigênico da Nefrite de Heymann , Humanos , Glomérulos Renais/imunologia , Glicoproteínas de Membrana/metabolismo , Dados de Sequência Molecular , Peso Molecular , Ratos , Homologia de Sequência de Aminoácidos , Domínios de Homologia de srcRESUMO
Diverse immunologic abnormalities have been described in women who received silicone breast implants. However, most studies have focused on either a limited number of patients or a small panel of autoantibodies. We report the analysis of 20 autoantibodies in 116 women with implants and 134 controls. The patients ranged from 26- to 66-years-old, with a mean of 45.7 +/- 8.3 years; breast prostheses were in place for a mean of 15 +/- 5.6 years, with a range of 4 to 30, the chief complaints of the 116 patients included polyarthralgias, fatigue, myalgias, morning stiffness, and decreased memory. All 250 sera were tested blindly using a panel of 20 autoantigens including SS-A, SS-B, RNP, cardiolipin (CL), collagen types I, II and IV, phosphatidylserine (PS), myeloperoxidase (MPO), sulfatides (sulf), thyroglobulin (TG), gangliosides (GDIa;GM2), proteinase-3 (PR3), Jo-1, Sm, HPRPP-ribosomal phosphate, histones (H2AH2B), Scl-70 and glomerular basement membrane (NC-1). Values from individual patients were considered positive only when greater than 3 SD above the control mean. There was a statistically significant greater frequency of autoantibodies in women with implants for 15 of the 20 autoantigens; these were particularly striking for anti-H2AH2B, HPRPP, SS-A, SS-B, Scl-70, CL, PS, GM2, and NC-1. Many patients harbored several autoantibodies; 20% had four autoantibodies; 8% had six autoantibodies. The association of autoantibodies and implants suggests an adjuvant action of silicon/silicone byproducts.
Assuntos
Adjuvantes Imunológicos , Autoanticorpos/sangue , Doenças Autoimunes/etiologia , Implantes de Mama/efeitos adversos , Doenças Reumáticas/etiologia , Silicones/efeitos adversos , Adulto , Idoso , Especificidade de Anticorpos , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Membrana Basal/imunologia , Doenças Mamárias , Colágeno/imunologia , Feminino , Géis , Humanos , Glomérulos Renais/imunologia , Pessoa de Meia-Idade , Poliuretanos , Falha de Prótese , Doenças Reumáticas/imunologia , Método Simples-Cego , Cloreto de Sódio , Tireoglobulina/imunologia , Fatores de TempoRESUMO
Cyclosporin A (CsA) can reduce proteinuria in various forms of human and experimental glomerulonephritis. This antiproteinuric effect of CsA may be the consequence of diminution of immunological damage, a drug-induced decrease of GFR, or changes in permselectivity of the glomerular basement membrane (GBM). We studied the antiproteinuric effect of CsA in the heterologous phase of a passively induced anti-GBM nephritis in the mouse. This passive model is characterized by acute exudative glomerular lesions and a dose-dependent albuminuria. Rabbit anti-mouse GBM antibodies were administered intravenously in C57B110 mice at day 4, after 3 days of pretreatment with either CsA (75 mg/kg body weight) (n = 15) or olive oil (OO, controls, n = 15) orally. CsA did not influence the severity of the histological lesions. Albuminuria was substantially reduced by CsA (CsA 1.6 +/- 1.8; OO 5.6 +/- 3.2 mg/18 h; P < 0.002). There was a considerable concomitant reduction of the GFR by CsA, as measured with a 51Cr-EDTA single-shot plasma clearance technique before (day-1) and during treatment (day 4): GFR ratio day 4/day-1 for CsA, 0.4 +/- 0.1; for OO controls, 1.1 +/- 0.6; P < 0.01. This drug-induced decrease of GFR was prevented by simultaneous treatment with phenoxybenzamine (PB) twice daily 45 micrograms orally for 4 days (GFR ratio day 4/day-1 for PB and CsA, 0.9 +/- 0.4; controls (PB and OO), 1.0 +/- 0.4; P = NS). Although the CsA-induced GFR reduction was prevented, CsA still reduced albuminuria significantly (PB and CsA, 2.2 +/- 1.8; controls (PB and OO), 5.6 +/- 1.8 mg/18 h; P = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Albuminúria/tratamento farmacológico , Anticorpos/imunologia , Ciclosporina/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomérulos Renais/imunologia , Nefrite/imunologia , Animais , Membrana Basal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/patologia , Nefrite/urina , CoelhosRESUMO
Podocytes are specialized epithelial cells with delicate interdigitating foot processes which cover the exterior basement membrane surface of the glomerular capillary. They are in part responsible for the extraordinary charge and size filtration characteristics of the glomerulus. To better understand disease processes affecting the glomerular filter, we searched for proteins with relative specificity to the podocyte using a monoclonal antibody strategy. The first such protein characterized (designated glomerular epithelial protein 1 (GLEPP1)) is a membrane protein-tyrosine phosphatase (PTPase) with a large extracellular domain containing eight fibronectin type III-like repeats, a hydrophobic transmembrane segment, and a single PTPase domain. The GLEPP1 PTPase domain shows homology with two other single domain transmembrane PTPases (PTP beta and Drosophila central nervous system PTP10D). This homology includes 2 cysteines in the PTPase domain not present in intracellular or tandem domain membrane PTPases. GLEPP1 PTPase protein is distributed to the podocyte foot processes themselves. RNase protection assay shows that GLEPP1 mRNA is also present in brain. By analogy with the CD45 PTPase of T cells, we expect that this receptor might play a role in maintaining foot process structure and/or function by regulating tyrosine phosphorylation of podocyte proteins.