RESUMO
Mesangial cells stimulated with high glucose (HG) exhibit increased intracellular angiotensin II (AngII) synthesis that is correlated with the upregulation of AngII target genes, such as profibrotic cytokines. The intracrine effects of AngII can be mediated by several molecules transferred to other cells via exosomes (Exos), which play a key role in cellular communication under many physiological and pathological conditions. The aim of this study was to investigate the effects of exosomes derived from HG-stimulated human mesangial cells (HG-HMCs) on normal unstimulated HMCs. Exosomes from HMCs (C-Exos) and HG-HMCs (HG-Exos) were obtained from cell culture supernatants. HMCs were incubated with C-Exos or HG-Exos. HG stimulus induced a change in the amount but not the size of Exos. Both C-Exos and HG-Exos contained angiotensinogen and renin, but no angiotensin converting enzyme was detected. Compared with HMCs treated with C-Exos, HMCs treated with HG-Exos presented higher levels of fibronectin, angiotensinogen, renin, AT1 and AT2 receptors, indicating that HG-Exos modified the function of normal HMCs. These results suggest that the intercellular communication through Exos may have pathophysiological implications in the diabetic kidney.
Assuntos
Angiotensina II/genética , Comunicação Celular/genética , Nefropatias Diabéticas/genética , Exossomos/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Exossomos/patologia , Fibronectinas/genética , Regulação da Expressão Gênica/genética , Mesângio Glomerular/metabolismo , Glucose/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Células Mesangiais/metabolismo , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Renina/genéticaRESUMO
Immunoglobulin A nephropathy (IgAN) was defined as a mesangiopathic disease, since the primary site of deposition of IgA immune material is the mesangium, and proliferation of mesangial cells and matrix excess deposition are the first histopathologic lesions. However, the relentless silent progression of IgAN is mostly due to the development of persistent proteinuria, and recent studies indicate that a major role is played by previous damage of function and anatomy of podocytes. In IgAN, the podocytopathic changes are the consequence of initial alterations in the mesangial area with accumulation of IgA containing immune material. Podocytes are therefore affected by interactions of messages originally driven from the mesangium. After continuous insult, podocytes detach from the glomerular basement membrane. This podocytopathy favours not only the development of glomerular focal and segmental sclerosis, but also the progressive renal function loss. It is still debated whether these lesions can be prevented or cured by corticosteroid/immunosuppressive treatment. We aimed to review recent data on the mechanisms implicated in the podocytopathy present in IgAN, showing new molecular risk factors for progression of this disease. Moreover, these observations may indicate that the target for new drugs is not only focused on decreasing the activity of mesangial cells and inflammatory reactions in IgAN, but also on improving podocyte function and survival.
Assuntos
Mesângio Glomerular/patologia , Glomerulonefrite por IGA/fisiopatologia , Podócitos/patologia , Proteinúria/etiologia , Animais , Progressão da Doença , Glomerulonefrite por IGA/complicações , Humanos , Proteinúria/patologiaAssuntos
Glomerulonefrite Membranoproliferativa , Glomerulonefrite , Biópsia , Criança , China , Mesângio Glomerular , Humanos , NefropatiasRESUMO
BACKGROUND: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN. METHODS: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50% or more. RESULTS: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50% decline in eGFR was 13% over 10 years. Nine children exhibited the primary outcome and 4 developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n = 37), C4d-positive patients (n = 10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, p < 0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 ml/min/1.73 m2/year; p = 0.045), and more frequently achieved the primary outcome (50.0 vs 10.8%, p = 0.013), and ESRD (30.0 vs 2.7%, p = 0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, p < 0.001). CONCLUSIONS: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.
Assuntos
Complemento C4b/análise , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/patologia , Falência Renal Crônica/patologia , Fragmentos de Peptídeos/análise , Biomarcadores/análise , Biomarcadores/metabolismo , Biópsia , Criança , Complemento C4b/metabolismo , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Mesângio Glomerular/metabolismo , Glomerulonefrite por IGA/urina , Humanos , Imuno-Histoquímica , Falência Renal Crônica/urina , Masculino , Fragmentos de Peptídeos/metabolismo , Prognóstico , Proteinúria/urina , Estudos Retrospectivos , Fatores de RiscoRESUMO
The incidence and prevalence of paraneoplastic glomerulopathy, especially associated with carcinoma, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. The aim of this study was to evaluate renal biopsies of selected bitches with spontaneous mammary gland carcinoma. We hypothesized that dogs with mammary carcinomas would show histologic evidence of glomerular pathology. A prospective study was performed in dogs with naturally occurring mammary carcinoma that were undergoing tumor resection and ovariohysterectomy. We evaluated renal biopsies of 32 bitches with spontaneous mammary gland carcinoma and 11 control dogs without mammary gland neoplasia. Samples were obtained from the left kidney and the biopsy material was divided for light microscopy (LM), immunofluorescence (IF) and transmission electron microscopy (TEM). Light microscopy abnormalities were identified in 78.1% of dogs with mammary carcinoma (n = 25) and in none of the dogs in the control group. Focal glomerular mesangial matrix expansion was the most common alteration (n = 15, 60.0%), but mesangial cell proliferation (n = 9, 36.0%) and focal segmental glomerulosclerosis (n = 9, 36.0%), synechiae (n = 7, 28.0%), and globally sclerotic glomeruli (n = 6, 24.0%) were also frequent in dogs with malignancy. Immunofluorescence microscopy revealed strong IgM staining was demonstrated in 64.3% (n = 18) of carcinoma dogs. Transmission electron microscopy from dogs with carcinoma revealed slight changes, the most frequent of which was faint sub-endothelial and mesangial deposits of electron-dense material (78%). Mesangial cell interpositioning and segmental effacement of podocyte foot processes were identified in some specimens (45%). Changes in the glomerulus and proteinuria are common in dogs with naturally occurring mammary carcinoma and this condition appears to provide an excellent large animal model for cancer-associated glomerulopathy in humans.
Assuntos
Doenças do Cão/epidemiologia , Glomerulonefrite/epidemiologia , Neoplasias Mamárias Animais/patologia , Animais , Doenças do Cão/patologia , Cães , Feminino , Mesângio Glomerular/patologia , Mesângio Glomerular/ultraestrutura , Glomerulonefrite/complicações , Glomerulonefrite/patologia , Imunoglobulina M/metabolismo , Rim/patologia , Neoplasias Mamárias Animais/complicações , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microscopia de Polarização , Prevalência , Estudos Prospectivos , Proteinúria/complicações , Proteinúria/patologiaRESUMO
Notch pathway activation in podocytes has been shown to play an important role in diabetic kidney disease (DKD) development; however, the receptors and ligands involved in the process have not been identified. Here, we report that conditional deletion of Notch1 in podocytes using NPHS2(cre)Notch1(flox/flox) animals resulted in marked amelioration of DKD. On the contrary, podocyte-specific genetic deletion of Notch2 had no effect on albuminuria and mesangial expansion. Notch1-null podocytes were protected from apoptosis and dedifferentiation in vitro, likely explaining the protective phenotype in vivo. Deletion of Notch1 in podocytes also resulted in an increase in Notch2 expression, indicating an interaction between the receptors. At the same time, transgenic overexpression of Notch2 in podocytes did not induce phenotypic changes, while constitutive expression of Notch1 caused rapid development of albuminuria and glomerulosclerosis. In summary, our studies indicate that Notch1 plays a distinct (nonredundant) role in podocytes during DKD development.
Assuntos
Apoptose , Desdiferenciação Celular , Nefropatias Diabéticas/metabolismo , Mesângio Glomerular/metabolismo , Podócitos/metabolismo , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular Transformada , Células Cultivadas , Cruzamentos Genéticos , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Mesângio Glomerular/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Podócitos/patologia , Domínios e Motivos de Interação entre Proteínas , RNA Mensageiro/metabolismo , Receptor Notch1/química , Receptor Notch1/genética , Receptor Notch2/química , Receptor Notch2/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMO
Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as hormone refractory. In recent years, the concept of hormone refractoriness has been challenged and replaced by castration resistance, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.
Assuntos
Animais , Ratos , Angiotensina II/fisiologia , Fibronectinas/biossíntese , Células Mesangiais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Poli(ADP-Ribose) Polimerases/fisiologia , Células Cultivadas , Fibronectinas/genética , Regulação Enzimológica da Expressão Gênica , Mesângio Glomerular/citologia , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Células Mesangiais/enzimologia , Células Mesangiais/patologia , Inibidor 1 de Ativador de Plasminogênio/genética , Poli(ADP-Ribose) Polimerases/biossíntese , Poli(ADP-Ribose) Polimerases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
INTRODUCTION: IgM nephropathy (IgMN) is a glomerulonephritis characterised by diffuse mesangial immunoglobulin M (IgM) deposits. It usually presents with nephrotic range proteinuria and, according to some previous work, it occurs most often in patients who are resistant to or dependent on steroid treatment. OBJECTIVE: To perform a clinical, histological and immunopathological description and assess the response to steroid treatment of paediatric patients diagnosed with nephrotic syndrome and diffuse mesangial IgM deposits. METHOD: This is a descriptive, retrospective study carried out in two hospitals, where the clinical records of paediatric patients with IgMN were analysed and the histological sections were re-assessed. RESULTS: thirteen children were included in this study. IgMN corresponded to 5.17% of all paediatric renal biopsies. The age of patients ranged from 1 year to 12 years (median: 2 years), 46.7% were women. The most common morphological finding was diffuse mesangial hypercellularity (46.1%), followed by focal segmental glomerulosclerosis (30.8%) and minimal glomerular changes (23.1%). All patients received steroids; in 4 cases (30.7%) as the only immunosuppressant medication, 3 (23.1%) also received cyclophosphamide, 5 (38.4%) mycophenolate, and 1 (7.7%) cyclosporine. Seven patients (53.8%) had frequent relapses, 5 (38.5%) were cortico-resistant and 1 (7.7%) cortico-dependent. Two patients (15.38%) had chronic impairment of renal function. CONCLUSION: The presence of diffuse mesangial IgM in paediatric patients with nephrotic syndrome is not a very uncommon finding; its clinical presentation has been associated with lower response to steroids. However, the long-term prognosis of these patients is still unknown.
Assuntos
Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Imunoglobulina M , Criança , Pré-Escolar , Feminino , Mesângio Glomerular/metabolismo , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Humanos , Imunoglobulina M/metabolismo , Lactente , Masculino , Estudos RetrospectivosRESUMO
A insuficiência renal crônica (IRC) é caracterizada por alterações glomerulares secundárias aos mecanismos adaptativos ocasionados por perda de néfrons funcionantes. Alterações na hemodinâmica glomerular, proliferação celular, influxo de células inflamatórias, desequilíbrio na síntese de proteínas da matriz extracelular glomerular (MECG) e perda da seletividade de carga e/ou tamanho da membrana basal glomerular têm sido apontados como mecanismos envolvidos na expansão mesangial e conseqüente glomeruloesclerose. A participação dos hormônios sexuais na função renal e na evolução da insuficiência renal crônica tem sido sugerida. Os glicosaminoglicanos, especialmente o heparan sulfato (HS), têm sido associados à seletividade glomerular de macromoléculas. O remodelamento podocitário precoce e a proteinuria (PTN) se relacionam com a progressão da IRC. Neste contexto, o acúmulo de MECG, proliferação de miofibroblastos e PTN têm sido apontados como mediadores precoces que precedem as lesões glomerulares e túbulo-intersticiais. Neste estudo, avaliamos as alterações renais precoces (30 dias de IRC) gênero-dependentes em ratos (M) e ratas (F) Wistar submetidos à redução de 5/6 da massa renal (IRC) e à castração (c). Os animais foram divididos em 10 grupos: Controles (C) (CM, CF, CMc, CFc) e sham (CM sham, CF sham); e aqueles submetidos à nefrectomia 5/6: IRCM, IRCF, IRCMc, IRCFc. Os animais foram castrados com 5 semanas e submetidos à nefrectomia 5/6 com 7 semanas de idade. Resultados significativos mostraram que os machos com IRC apresentaram maior PTN, acompanhada de maior comprometimento mesangial, imunomarcação positiva para α-actina e maior concentração de heparan sulfato (HS) comparados com as fêmeas IRC (p<0,05). Estas alterações foram reduzidas nos machos castrados. A análise da morfologia podocitária mostrou raras regiões onde ocorreram alterações podocitárias nos grupos IRC. O conjunto de dados sugere que o hormônio masculino pode participar na manutenção...
Chronic renal failure (CRF) is characterized by adaptive mechanisms secondary to the loss of functioning nephrons. Glomerular hemodynamics alterations, cellular proliferation, inflammatory cells influx, imbalance between synthesis and degradation of the glomerular extracellular matrix (GECM) and loss of charge and/or size selectivity of the glomerular basal membrane are pointed as mechanisms leading to mesangial expansion and glomerulosclerosis. Additionally, participation of gender related hormones on renal function and progression of CRF have been suggested. We evaluated the effect of castration in renal alterations in males (M) and females (F) Wistar rats, after 30 days of 5/6 reduction of renal mass (CRF). The animals were castrated (c) at 5 weeks old and 7 weeks old 5/6 and sham nephrectomy were done. Groups: Control (C) CM, CM sham, CMc, CF, CF sham, CFc, CRFM, CRFMc, CRFF, CRFFc. CRFM group showed higher proteinuria followed by increased mesangial expansion and α-actin immunostaining. Concomitant higher concentration of heparan sulfate (HS) was also observed when compared to CRFF (p<0.05). These alterations were reduced in CRFMc group. Podocyte morphology analysis through electronic microscopy showed few disorders of foot processes in CRF groups Overall, CRFF group showed fewer alterations compared to males, and a reduction of HS was observed in association with PTN. Castration did not change this profile in female rats. Data suggest that male hormones may participate in the maintenance of the mesangial equilibrium and that PTN collaborated with the mesangial expansion process. Additionally, the higher concentration of HS in CRFM suggest that the remodeling process of the GECM, included a synthesis of de novo HS, that presented a functioning defect, compromising the glomerular filtration barrier and, ultimately corroborated with the loss of its selectivity and consequently with a higher PTN. This set of results leads us to conclude that PTN appears...
Assuntos
Animais , Ratos , Insuficiência Renal Crônica , Rim/fisiopatologia , Mesângio Glomerular , Glicosaminoglicanos , Glomérulos Renais/lesões , Miofibroblastos , Matriz Extracelular/metabolismo , Nefrectomia , Proteinúria , Proliferação de Células , Ratos Wistar , Fatores SexuaisRESUMO
BACKGROUND: The renal manifestations of IgA nephropathy are wide, including patients with asymptomatic disease. The probability of developing advanced renal disease after 20 years of diagnosis varies. The prevalence of mesangial deposits of IgA in otherwise healthy people has been studied previously and there are only 2 reports in which the diagnosis is made by time-zero renal biopsy (TO-RBx). MATERIAL AND METHODS: We compared clinical characteristics (baseline and at followup) of renal donors with IgA nephropathy diagnosed by TO-RBx compared with 20 donors with normal TO-RBx. RESULTS: From 1999 to 2006 151 T0-RBx were analyzed. Of these 10 cases (6.62%) had IgA nephropathy. There were two patients with stage II and 8 with stage I according to HASS classification of IgA nephropathy. All donors in both groups (n=30) had normal urinary tests, however urinary protein excretion was significantly higher in the IgA nephropathy group compared with the normal group from baseline to the end of follow-up (three years). The glomerular filtration rate at three years of follow-up was significantly higher in the normal group (80 +/- 14 vs. 65 +/- 8 mL/min, p = 0.001). CONCLUSIONS: Donors with IgA nephropathy on TO-RBx had no urinary abnormalities during pre donation screening. At three years of follow-up patients with IgA nephropathy showed a greater loss of renal function as well as increased urinary protein excretion.
Assuntos
Glomerulonefrite por IGA/diagnóstico , Transplante de Rim , Doadores Vivos , Nefrectomia , Complicações Pós-Operatórias/diagnóstico , Adulto , Biópsia , Colesterol/sangue , Diagnóstico Tardio , Diagnóstico Precoce , Feminino , Seguimentos , Taxa de Filtração Glomerular , Mesângio Glomerular/imunologia , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Prevalência , Proteinúria/etiologia , Índice de Gravidade de Doença , Triglicerídeos/sangueRESUMO
Previous reports have shown that angiotensin II and oxidative stress may be important features in acute poststreptococcal glomerulonephritis (APSGN) and that streptococcal erythrogenic toxin type B (ETB) and its precursor (ETBP) may have an important role in the pathogenesis of APSGN. The aim of this study was to determine the effect of ETBP on the production of angiotensin II and oxidative stress in rat mesangial cells and human mononuclear leukocytes. Mesangial cells and leukocytes were isolated from digested glomeruli and by histopaque gradient, respectively, while ETBP was isolated from nephritogenic streptococcus cultures using a cation exchange column. Angiotensin II was determined by an enzyme-linked immunosorbent assay and by cytometrics. Superoxide anion, reduced glutathione, nitrites, lipid peroxidation and catalase activity were determined by cytochemical, biochemical and enzymatic assays. Inducible nitric oxide synthase expression was determined by cytometrics. An increased production of angiotensin II was observed in ETBP-treated mesangial cell and leukocyte cultures. The ETBP induced an elevated production of superoxide anions and nitrites in mesangial cells and superoxide anions in leukocytes, while this streptococcal protein decreased the expression of inducible nitric oxide synthase in leukocytes. The ETBP was capable of inducing an increased production of angiotensin II and increased oxidative stress, both of which may be important mediators of inflammatory events in the renal tissue and during APSGN.
Assuntos
Angiotensina II/biossíntese , Proteínas de Bactérias/farmacologia , Exotoxinas/farmacologia , Mesângio Glomerular/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Animais , Catalase/metabolismo , Separação Celular , Células Cultivadas , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glutationa/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
In routine diagnosis for renal biopsy, glomerular diseases are encountered that, viewed by electron microscopy, reveal deposits with a fibrillary structure in the extracellular matrix of the glomeruli. Amyloidosis is the most common glomerulopathy that shows deposits with an ultrastructural fibrillary structure. However, other glomerulopathies have deposits with an ultrastructural fibrillary structure and which are negative for Congo-red stain, but positive for immunoglobulins. Fibrillary glomerulonephritis is a well-characterized disease, and clearly identified in approximately 0.5% to 1% of biopsies of native kidneys. These cases usually manifest themselves as severe renal insufficiencies with nephrotic-range proteinuria. No treatment regimes have been clearly established and the prognosis is poor. Herein, the clinical and histological characteristics are described for the first case of idiopathic fibrillary glomerulonephritis reported in Colombia.
Assuntos
Glomerulonefrite/patologia , Corpos de Inclusão/ultraestrutura , Nefrite Intersticial/patologia , Colômbia/epidemiologia , Terapia Combinada , Mesângio Glomerular/química , Mesângio Glomerular/ultraestrutura , Glomerulonefrite/complicações , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/epidemiologia , Humanos , Hipertensão/complicações , Imunossupressores/uso terapêutico , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/complicações , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/tratamento farmacológico , Síndrome Nefrótica/etiologia , Obesidade/complicações , Diálise PeritonealRESUMO
We report the case of a 10-year-old girl presenting with linear IgA disease of childhood who in the follow-up at age 16 developed hematuria and proteinuria resulting from IgA nephropathy. The combination of linear IgA disease and Berger nephropathy appears to be extremely uncommon but clinical alertness to this association might discover additional cases.
Assuntos
Mesângio Glomerular/imunologia , Glomerulonefrite por IGA/complicações , Imunoglobulina A/análise , Dermatopatias Vesiculobolhosas/complicações , Pele/imunologia , Criança , Feminino , Técnica Direta de Fluorescência para Anticorpo , Seguimentos , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/diagnóstico , Humanos , Pele/patologia , Dermatopatias Vesiculobolhosas/diagnósticoRESUMO
Multipotent mesenchymal stromal cells (MSCs), often labeled mesenchymal stem cells, contribute to tissue regeneration in injured bone and cartilage, as well as in the infarcted heart, brain, and kidney. We hypothesize that MSCs might also contribute to pancreas and kidney regeneration in diabetic individuals. Therefore, in streptozotocin (STZ)-induced type 1 diabetes C57BL/6 mice, we tested whether a single intravenous dose of MSCs led to recovery of pancreatic and renal function and structure. When hyperglycemia, glycosuria, massive beta-pancreatic islets destruction, and mild albuminuria were evident (but still without renal histopathologic changes), mice were randomly separated in 2 groups: 1 received 0.5 x 10(6) MSCs that have been ex vivo expanded (and characterized according to their mesenchymal differentiation potential), and the other group received the vehicle. Within a week, only MSC-treated diabetic mice exhibited significant reduction in their blood glucose levels, reaching nearly euglycemic values a month later. Reversion of hyperglycemia and glycosuria remained for 2 months at least. An increase in morphologically normal beta-pancreatic islets was observed only in MSC-treated diabetic mice. Furthermore, in those animals albuminuria was reduced and glomeruli were histologically normal. On the other side, untreated diabetic mice presented glomerular hyalinosis and mesangial expansion. Thus, MSC administration resulted in beta-pancreatic islets regeneration and prevented renal damage in diabetic animals. Our preclinical results suggest bone marrow-derived MSC transplantation as a cell therapy strategy to treat type 1 diabetes and prevent diabetic nephropathy, its main complication.
Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Nefropatias Diabéticas/prevenção & controle , Hiperglicemia/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Multipotentes/transplante , Adipócitos/citologia , Albuminúria/etiologia , Albuminúria/prevenção & controle , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/patologia , Mesângio Glomerular/patologia , Hiperglicemia/etiologia , Infusões Intravenosas , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiologia , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Osteócitos/citologia , Distribuição Aleatória , Regeneração , Células Estromais/transplanteRESUMO
The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.
Assuntos
Nefropatias Diabéticas/etiologia , Mesângio Glomerular , Hiperglicemia/complicações , Angiotensina II/metabolismo , Proliferação de Células/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Transportador de Glucose Tipo 1/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Esclerose/metabolismo , Esclerose/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Vasoconstritores/metabolismoRESUMO
O principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-beta1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-beta1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes - e aditivos - na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional.
The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.
Assuntos
Humanos , Nefropatias Diabéticas/etiologia , Mesângio Glomerular , Hiperglicemia/complicações , Angiotensina II/metabolismo , Proliferação de Células/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Transportador de Glucose Tipo 1/metabolismo , /metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Esclerose/metabolismo , Esclerose/fisiopatologia , Fator de Crescimento Transformador beta1/metabolismo , Vasoconstritores/metabolismoRESUMO
Renal involvement in visceral leishmaniasis (VL) is very frequent but the pathogenesis of this nephropathy is poorly understood. In previous studies using dogs with VL we have detected new immunopathological elements in the glomeruli such as T cells and adhesion molecules. Although Leishmania (Leishmania) chagasi-infected dogs and hamsters are considered to be good models for VL, their use is limited for immunopathologic studies. The use of isogenic mouse strains susceptible to L. (L.) chagasi infection was an alternative but, on the other hand, the renal lesions of these animals have not yet been characterized. Thus, our purpose in the present study was to characterize mice infected with L. (L.) chagasi as a suitable model to study VL nephropathy. Kidney samples were obtained from control mice (N = 12) and from BALB/c mice (N = 24) injected intraperitoneally with 20 million L. (L.) chagasi amastigotes 7, 15, and 30 days after injection and processed for histopathological studies and detection of IgG deposits. Glomerular hypercellularity was clearly visible and, upon Mason's trichrome and periodic acid methenamine silver staining, a pattern suggestive of mesangial proliferative glomerulonephritis was observed in mice with VL. Time-dependent IgG deposits were also seen in infected mice. We consider L. (L.) chagasi-infected mice to be a suitable model for studies of the immunopathogenesis of glomerular lesions in VL.
Assuntos
Modelos Animais de Doenças , Mesângio Glomerular/patologia , Glomerulonefrite/patologia , Leishmania infantum , Leishmaniose Visceral/patologia , Animais , Glomerulonefrite/parasitologia , Leishmaniose Visceral/complicações , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fatores de TempoRESUMO
Renal involvement in visceral leishmaniasis (VL) is very frequent but the pathogenesis of this nephropathy is poorly understood. In previous studies using dogs with VL we have detected new immunopathological elements in the glomeruli such as T cells and adhesion molecules. Although Leishmania (Leishmania) chagasi-infected dogs and hamsters are considered to be good models for VL, their use is limited for immunopathologic studies. The use of isogenic mouse strains susceptible to L. (L.) chagasi infection was an alternative but, on the other hand, the renal lesions of these animals have not yet been characterized. Thus, our purpose in the present study was to characterize mice infected with L. (L.) chagasi as a suitable model to study VL nephropathy. Kidney samples were obtained from control mice (N = 12) and from BALB/c mice (N = 24) injected intraperitoneally with 20 million L. (L.) chagasi amastigotes 7, 15, and 30 days after injection and processed for histopathological studies and detection of IgG deposits. Glomerular hypercellularity was clearly visible and, upon Mason's trichrome and periodic acid methenamine silver staining, a pattern suggestive of mesangial proliferative glomerulonephritis was observed in mice with VL. Time-dependent IgG deposits were also seen in infected mice. We consider L. (L.) chagasi-infected mice to be a suitable model for studies of the immunopathogenesis of glomerular lesions in VL.
Assuntos
Animais , Masculino , Camundongos , Modelos Animais de Doenças , Mesângio Glomerular/patologia , Glomerulonefrite/patologia , Leishmania infantum , Leishmaniose Visceral/patologia , Glomerulonefrite/parasitologia , Leishmaniose Visceral/complicações , Camundongos Endogâmicos BALB C , Fatores de TempoAssuntos
Hematúria/etiologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/patologia , Anti-Hipertensivos/uso terapêutico , Biópsia , Ciclofosfamida/uso terapêutico , El Salvador/etnologia , Feminino , Seguimentos , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/ultraestrutura , Mesângio Glomerular/patologia , Mesângio Glomerular/ultraestrutura , Glucocorticoides/uso terapêutico , Hispânico ou Latino , Humanos , Hidroclorotiazida/uso terapêutico , Hidroxicloroquina/uso terapêutico , Hipertensão/tratamento farmacológico , Imunossupressores/uso terapêutico , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Lisinopril/uso terapêutico , Nefrite Lúpica/classificação , Nefrite Lúpica/tratamento farmacológico , Pessoa de Meia-Idade , Nifedipino/uso terapêutico , Prednisona/uso terapêutico , Tetrazóis/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Valina/análogos & derivados , Valina/uso terapêutico , ValsartanaRESUMO
Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.