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1.
Actas Urol Esp (Engl Ed) ; 45(2): 116-123, 2021 Mar.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33213957

RESUMO

INTRODUCTION: During the COVID-19 pandemic, the national transplant activity has been reduced due to the overload of the health system and concern for patient safety in this situation. The aim of our work is to expose the activity of kidney transplantation in Cantabria during the state of alarm, as well as to assess the safety of the transplantation program. MATERIAL AND METHODS: Retrospective study of kidney transplants performed in our Center from the beginning of the state of alarm until the beginning of the lockdown easing in Cantabria. Descriptive analysis of the demographic data of recipients and their donors, intraoperative data and postoperative outcomes. Comparative analysis with the data of the same period in 2017-2019, by means of the χ2 for categorical variables, Student's T and Mann-Whitney U tests in case of quantitative variables of normal and non-normal distribution, respectively. RESULTS: Fifteen kidney transplants were performed in the period described. Delayed renal function (DRF) was seen in 7.5% of patients, and 26.6% showed data of acute rejection; no patient presented COVID-19 disease. Comparative analysis showed a remarkable increase in the number of transplants in comparison with previous periods (15 vs 5.6), at the expense of donors from outside Cantabria (93.3%). We found no statistically significant differences in terms of cold ischemia time (p=0.77), DRF (p=0.73), need for dialysis (p=0.54), or appearance of post-surgical complications (p=0.61). CONCLUSIONS: The evolution of the pandemic in our region, and the adoption of strict protective measures has allowed the early and safe resumption of the renal transplantation program, increasing the number of transplants performed compared to previous years and maintaining comparable early post-operative results.


Assuntos
COVID-19 , Transplante de Rim , Pandemias , Adulto , Soro Antilinfocitário/uso terapêutico , COVID-19/epidemiologia , COVID-19/prevenção & controle , Isquemia Fria , Comorbidade , Diabetes Mellitus/epidemiologia , Suscetibilidade a Doenças , Feminino , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/terapia , Humanos , Hipertensão/epidemiologia , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Nefropatias/cirurgia , Transplante de Rim/métodos , Transplante de Rim/estatística & dados numéricos , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/prevenção & controle , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Transplante de Pâncreas/estatística & dados numéricos , Plasmaferese , Terapia de Substituição Renal , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Risco , Espanha/epidemiologia , Resultado do Tratamento
2.
Kidney Int ; 93(4): 814-825, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29132705

RESUMO

Mesenchymal stem cells (MSCs) are effective for the management of experimental ischemia-reperfusion acute kidney injury (IRI-AKI). Immune modulation is one of the important mechanisms of MSCs treatment. Interleukin-17A (IL-17A) pretreated MSCs are more immunosuppressive with minimal changes in immunogenicity in vitro. Here, we demonstrated that administration of IL-17A-pretreated MSCs resulted in significantly lower acute tubular necrosis scores, serum creatinine, and BUN of mice with IRI-AKI, compared with the administration of MSCs. Of the co-cultured splenocytes, IL-17A-pretreated MSCs significantly increased the percentages of CD4+Foxp3+ Tregs and decreased concanavalin A-induced T cell proliferation. Furthermore, mice with IRI-AKI that underwent IL-17A-pretreated MSC therapy had significantly lower serum IL-6, TNF-α, and IFN-γ levels, a higher serum IL-10 level, and higher spleen and kidney Treg percentages than the mice that underwent MSCs treatment. Additionally, the depletion of Tregs by PC61 (anti-CD25 antibody) reversed the enhanced treatment efficacy of the IL-17A-pretreatedMSCs on mice with IRI-AKI. Additionally, IL-17A upregulated COX-2 expression and increased PGE2 production. The blockage of COX-2 by celecoxib reversed the benefit of IL-pretreated 17A-MSCs on the serum PGE2 concentration, spleen and kidney Tregs percentages, serum creatinine and BUN levels, renal acute tubular necrosis scores, and serum IL-6, TNF-α, IFN-γ, and IL-10 levels of IRI-pretreated mice with AKI, compared with MSCs. Thus, our results suggest that IL-17A pretreatment enhances the efficacy of MSCs on mice with IRI-AKI by increasing the Treg percentages through the COX-2/PGE2 pathway.


Assuntos
Proliferação de Células , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Interleucina-17/farmacologia , Necrose Tubular Aguda/prevenção & controle , Rim/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Linfócitos T Reguladores/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Células Cultivadas , Técnicas de Cocultura , Creatinina/sangue , Citocinas/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Rim/imunologia , Rim/patologia , Necrose Tubular Aguda/imunologia , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/patologia , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
3.
Kidney Int ; 91(2): 352-364, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27692564

RESUMO

Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet activation exacerbates acute kidney injury. However, the mechanism of platelet activation during ischemia reperfusion injury and how platelet activation leads to tissue injury are largely unknown. Here we found that renal ischemia reperfusion injury in mice leads to increased platelet activation in immediate proximity of necrotic cell casts. Furthermore, platelet inhibition by clopidogrel decreased cell necrosis and inflammation, indicating a link between platelet activation and renal tissue damage. Necrotic tubular epithelial cells were found to release extracellular DNA, which, in turn, activated platelets, leading to platelet-granulocyte interaction and formation of neutrophil extracellular traps ex vivo. Renal ischemia reperfusion injury resulted in increased DNA-platelet and DNA-platelet-granulocyte colocalization in tissue and elevated levels of circulating extracellular DNA and platelet factor 4 in mice. After renal ischemia reperfusion injury, neutrophil extracellular traps were formed within renal tissue, which decreased when mice were treated with the platelet inhibitor clopidogrel. Thus, during renal ischemia reperfusion injury, necrotic cell-derived DNA leads to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury.


Assuntos
Plaquetas/metabolismo , DNA/metabolismo , Células Epiteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Necrose Tubular Aguda/metabolismo , Túbulos Renais/metabolismo , Ativação Plaquetária , Traumatismo por Reperfusão/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Linhagem Celular , Clopidogrel , DNA/genética , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Necrose Tubular Aguda/genética , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Camundongos Endogâmicos C57BL , Nefrite/genética , Nefrite/metabolismo , Nefrite/patologia , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Fator Plaquetário 4/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia , Fatores de Tempo
4.
Kidney Int ; 91(2): 387-401, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789056

RESUMO

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition.


Assuntos
Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Progressão da Doença , Regulação Enzimológica da Expressão Gênica , Genótipo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Glutationa/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Necrose Tubular Aguda/genética , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/patologia , Túbulos Renais/patologia , Camundongos Knockout , NADP/metabolismo , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Fenótipo , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Fatores de Tempo , Transfecção
5.
Salvador; s.n; 2017. 100 p. ilus, tab.
Tese em Português | LILACS | ID: biblio-1001001

RESUMO

INTRODUCTION: Acute kidney injury (AKI) is a common complication in patients with nephrotic syndrome (NS), and it is reported in 34% of adults with idiopathic nephrotic syndrome. Emergence of AKI in the course of nephrotic syndrome requires a prompt differential diagnosis between acute tubular necrosis (ATN) and proliferative glomerular lesions leading to rapidly progressive glomerulonephritis. Although clinical and conventional laboratory clues can be decisive in many cases, sometimes such distinctions rely on renal biopsy, which is an invasive procedure and is not available in many centers. Several new biomarkers have emerged, increasing the perspective on early diagnosis and the prognostic prediction of AKI. OBJECTIVES: In this work, we studied the use of tests based on the urinary concentrations of kidney injury molecule-1 (KIM-1)...


INTRODUÇÃO: A lesão renal aguda (LRA) é uma complicação frequente em pacientes com glomerulopatias, acomentendo até 34% dos adultos com síndrome nefrótica (SNO) idiopática. O diagnóstico diferencial de necrose tubular aguda (NTA) de glomeulonefrite proliferativa ou crescêntica em pacientes com SNO e LRA é fundamental, visto que a NTA pode mimetizar quadro de glomerulonefrite rapidamente progressiva. Dados clínicos e laboratoriais podem ser úteis no diagnóstico diferencial da LRA na SNO, entretanto a distinção entre NTA e glomerulonefrite proliferativa ou crescêntica é feito pela biópsia renal, procedimento invasivo e que não está disponível amplamente. Novos biomarcadores para diagnóstico precoce e preditores diagnósticos na LRA têm sido identificados. OBJETIVOS: Neste trabalho nós avaliamos o uso de testes baseados nas concentrações urinárias de kidney injury molecule-1 (KIM-1)...


Assuntos
Humanos , Necrose Tubular Aguda/complicações , Necrose Tubular Aguda/diagnóstico , Necrose Tubular Aguda/imunologia , Necrose Tubular Aguda/mortalidade , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle , Síndrome Nefrótica/epidemiologia
6.
Ann Vasc Surg ; 32: 176-87, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26802296

RESUMO

BACKGROUND: The use of imaging is increasing in clinical practice either for diagnosis or intervention. In these aims, contrast medium (CM) is widely used. However, CM administration can induce contrast-induced nephropathy (CIN). The incidence of CIN varies from 2% to 50% depending on patient risk factors, and CIN is the third cause of renal insufficiency. To date, methods such as hyperhydration to prevent CIN have a low level of evidence. Remote ischemic preconditioning (RIPC), which has already proved its efficiency in the cardiology field, seems to be a promising technique for CIN prevention. The aim of this work was to carry out a systematic review of the literature of the randomized clinical studies on RIPC in the prevention of CIN in man. METHODS: We conducted a systematic review of randomized clinical studies on the RIPC in the prevention of CIN in man. Documentary sources were PubMed articles published until June 2015. Randomized clinical trials of RIPC in preventing CIN in human were reviewed. RESULTS: Five articles were selected for the analysis. One article studied the impact of RIPC in a population at high risk of CIN, whereas the other 4 analyzed populations at low, moderate or unknown risk of CIN. In 4 studies, except the later one, the risk of CIN was based on the Mehran score that was previously published. In the high-risk population, a decrease in the incidence of CIN was found in the RIPC group compared with the control group (12% against 40%; P = 0.002). Among the 3 other studies using the Mehran's score, one also demonstrated the interest of such a procedure in a subgroup of high-risk patients. A second one found a low incidence of CIN in the RIPC group ([5 of 47; 10%] as compared with a control group [17 of 47; 36%] P = 0.003) in patients at the low risk of CIN. In another low-risk population, a significant lower level of a biological marker (liver-type fatty acid-binding protein) that assesses a renal impairment was found in the RIPC compared with the control group. CONCLUSIONS: Only 5 studies were found in this search, which may constitute a limitation. However, RIPC appears as a promising method to prevent CIN since it is a noninvasive, low cost, easy, and safe method. More randomized controlled trials are needed to confirm these preliminary results.


Assuntos
Injúria Renal Aguda/prevenção & controle , Meios de Contraste/efeitos adversos , Precondicionamento Isquêmico/métodos , Necrose Tubular Aguda/prevenção & controle , Extremidade Superior/irrigação sanguínea , Acetilcisteína/administração & dosagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/fisiopatologia , Antioxidantes/administração & dosagem , Hidratação/métodos , Humanos , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/diagnóstico , Necrose Tubular Aguda/fisiopatologia , Fluxo Sanguíneo Regional , Fatores de Risco , Torniquetes , Resultado do Tratamento
7.
Salvador; s.n; 2015. 57 p. ilus, tab.
Tese em Português | LILACS | ID: biblio-1000965

RESUMO

Necrose tubular aguda (NTA) é a causa mais frequente de lesão renal aguda (LRA) em pacientes hospitalizados. Em pacientes com síndrome nefrótica (SNO), a NTA mimetiza, por vezes, quadro de glomerulonefrite rapidamente progressiva e requer instituição precoce de imunossupressores. A análise do sedimento urinário é uma ferramenta não invasiva, de baixo custo e ampla disponibilidade. O achado de células epiteliais no sedimento urinário de pacientes com LRA foi associado ao diagnóstico de NTA. Entretanto, estudos em pacientes com SNO associada são escassos. Técnicas de diagnóstico utilizando sedimento urinário corado normalmente não são utilizadas nesses casos. Além do mais, o sedimento urinário é uma importante fonte de proteínas; estudos proteômicos do sedimento urinário revelaram importantes frações de proteínas não encontradas em sobrenadante, que pode ser usado como potencial biomarcador de LRA. Nosso objetivo é identificar alterações citológicas e protéicas no sedimento urinário que permitam o diagnóstico diferencial entre NTA ou lesão inflamatória-proliferativa glomerular (INF) em pacientes com SNO. Trata-se de um estudo de corte transversal, onde foram incluídos 32 pacientes: 5 pacientes normais (grupo controle), 10 com NTA, 9 sem NTA e 8 com glomerulonefrites exsudativas. As células do sedimento urinário foram contadas, citocentrifugadas, coradas em hematoxilina/eosina ou Papanicolaou e contadas diferencialmente como pequenas (<30μm de diâmetro), médias (30-48μm)...


Acute tubular necrosis (ATN) is the most frequent cause of acute kidney injury (AKI) in hospitalized patients. In patients with nephrotic syndrome (NS), acute tubular necrosis mimic, sometimes, rapidly progressive glomerulonephritis and requires premature institution of immunosuppressive treatment. The analysis of urinary sediment is a noninvasive tool, low cost and wide availability. The found of epithelial cells in the urinary sediment of patients with AKI was associated to ATN diagnosis. However, studies in patients with AKI in the set of NS are scarce. Diagnostics techniques using stained urinary sediment are not ordinarily used in these cases. Furthermore, urinary sediment is an important source of proteins; proteomic studies revealed important fractions of proteins not found in urinary supernatant that could be used as potential biomarkers for AKI. Our goal is identify cytological alterations and protein in urinary sediment which allow the differential diagnosis between ATN and inflammatory-proliferative glomerular lesion (INF) in patients with NS. This is a cross sectional study, in which 32 patients were included: 5 normal patients (control group), 10 with ATN, 9 without ATN and 8 with exudative glomerulonephritis. The cells of urinary sediment were counted, cytocentrifuged, stained of hematoxylin/eosin or Papanicolaou and differentially counted as small (<30μm of diameter), medium (30-48μm)...


Assuntos
Humanos , Glomerulonefrite/diagnóstico , Glomerulonefrite/epidemiologia , Glomerulonefrite/urina , Necrose Tubular Aguda/diagnóstico , Necrose Tubular Aguda/epidemiologia , Necrose Tubular Aguda/imunologia , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle
8.
J Thorac Cardiovasc Surg ; 148(2): 690-697.e3, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24521949

RESUMO

OBJECTIVES: Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. METHODS: A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells. RESULTS: Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. CONCLUSIONS: Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury.


Assuntos
Injúria Renal Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Ponte Cardiopulmonar/efeitos adversos , Inflamação/prevenção & controle , Isotiocianatos/farmacologia , Necrose Tubular Aguda/prevenção & controle , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Inflamação/sangue , Inflamação/etiologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/etiologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , NF-kappa B/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos , Suínos , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
J Am Soc Nephrol ; 24(3): 445-55, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23393318

RESUMO

Elevated levels of plasma catecholamines accompany ischemic AKI, possibly contributing the inflammatory response. Renalase, an amine oxidase secreted by the proximal tubule, degrades circulating catecholamines and reduces myocardial necrosis, suggesting that it may protect against renal ischemia reperfusion injury. Here, mice subjected to renal ischemia reperfusion injury had significantly lower levels of renalase in the plasma and kidney compared with sham-operated mice. Consistent with this, plasma NE levels increased significantly after renal ischemia reperfusion injury. Furthermore, renal tubular inflammation, necrosis, and apoptosis were more severe and plasma catecholamine levels were higher in renalase-deficient mice subjected to renal ischemia reperfusion compared with wild-type mice. Administration of recombinant human renalase reduced plasma catecholamine levels and ameliorated ischemic AKI in wild-type mice. Taken together, these data suggest that renalase protects against ischemic AKI by reducing renal tubular necrosis, apoptosis, and inflammation, and that plasma renalase might be a biomarker for AKI. Recombinant renalase therapy may have potential for the prevention and treatment of AKI.


Assuntos
Injúria Renal Aguda/prevenção & controle , Isquemia/prevenção & controle , Monoaminoxidase/farmacologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Isquemia/metabolismo , Isquemia/patologia , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monoaminoxidase/deficiência , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Norepinefrina/sangue , Fentolamina/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle
10.
Kidney Int ; 83(4): 635-46, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23325074

RESUMO

Adrenocorticotropic hormone (ACTH) has a renoprotective effect in chronic kidney disease; however, its effect on acute kidney injury (AKI) remains unknown. In a rat model of tumor necrosis factor (TNF)-induced AKI, we found that ACTH gel prevented kidney injury, corrected acute renal dysfunction, and improved survival. Morphologically, ACTH gel ameliorated TNF-induced acute tubular necrosis, associated with a reduction in tubular apoptosis. While the steroidogenic response to ACTH gel plateaued, the kidney-protective effect continued to increase at even higher doses, suggesting steroid-independent mechanisms. Of note, ACTH also acts as a key agonist of the melanocortin system, with its cognate melanocortin 1 receptor (MC1R) abundantly expressed in renal tubules. In TNF-injured tubular epithelial cells in vitro, ACTH reinstated cellular viability and eliminated apoptosis. This beneficial effect was blunted in MC1R-silenced cells, suggesting that this receptor mediates the anti-apoptotic signaling of ACTH. Moreover, ACTH gel protected mice against cecal ligation puncture-induced septic AKI better than α-melanocyte-stimulating hormone: a protein equal in biological activity to ACTH except for steroidogenesis. Thus, ACTH has additive renoprotective actions achieved by both steroid-dependent mechanisms and MC1R-directed anti-apoptosis. ACTH may represent a novel therapeutic strategy to prevent or treat AKI.


Assuntos
Injúria Renal Aguda/prevenção & controle , Hormônio Adrenocorticotrópico/farmacologia , Corticosterona/sangue , Rim/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/microbiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Ceco/microbiologia , Ceco/cirurgia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Géis , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/metabolismo , Rim/microbiologia , Rim/patologia , Rim/fisiopatologia , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Ligadura , Masculino , Camundongos , Punções , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Tipo 1 de Melanocortina/genética , Receptor Tipo 1 de Melanocortina/metabolismo , Fatores de Tempo , Transfecção , Fator de Necrose Tumoral alfa , Regulação para Cima
11.
Kidney Int ; 83(4): 647-61, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23325083

RESUMO

Ischemia-reperfusion activates innate immunity and sterile inflammation, resulting in acute kidney injury. Since pentraxin 3 (PTX3) regulates multiple aspects of innate immunity and tissue inflammation, we tested whether PTX3 would be involved in renal ischemia-reperfusion injury. Renal pedicle clamping increased PTX3 serum levels, as well as PTX3 expression, inside the kidney but predominantly in CD45/CD11c(+) cells, a subpopulation of intrarenal mononuclear phagocytes. Lack of PTX3 aggravated postischemic acute kidney injury as evidenced by massive tubular necrosis, and TNF and IL-6 release, as well as massively increased neutrophil and macrophage infiltrates at 24 h. This was followed by tubular atrophy, interstitial fibrosis, and kidney shrinking 10 weeks later. In vivo microscopy uncovered increased leukocyte adhesion and transmigration in postischemic microvessels of Ptx3-deficient mice. Furthermore, injection of recombinant PTX3 up to 6 h after reperfusion prevented renal leukocyte recruitment and postischemic kidney injury. Thus, local PTX3 release from a subpopulation of intrarenal mononuclear phagocytes or delayed PTX3 treatment limits postischemic renal inflammation. Conversely, Ptx3 loss-of-function mutations predispose to postischemic acute kidney injury and subsequent chronic kidney disease.


Assuntos
Injúria Renal Aguda/prevenção & controle , Proteína C-Reativa/metabolismo , Rim/irrigação sanguínea , Rim/imunologia , Proteínas do Tecido Nervoso/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/sangue , Injúria Renal Aguda/genética , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Animais , Atrofia , Proteína C-Reativa/administração & dosagem , Proteína C-Reativa/deficiência , Proteína C-Reativa/genética , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibrose , Mediadores da Inflamação/metabolismo , Injeções , Interleucina-6/metabolismo , Rim/patologia , Necrose Tubular Aguda/imunologia , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/prevenção & controle , Leucócitos/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/administração & dosagem , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Infiltração de Neutrófilos , Selectina-P/metabolismo , Proteínas Recombinantes/administração & dosagem , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Fatores de Tempo , Migração Transendotelial e Transepitelial , Fator de Necrose Tumoral alfa/metabolismo
12.
Kidney Int ; 82(10): 1105-13, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22854641

RESUMO

Experimental aristolochic acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro, probenecid inhibits aristolochic acid entry through organic anion transporters, reduces specific aristolochic acid-DNA adduct formation, and preserves cellular viability. To test this in vivo, we used a mouse model of aristolochic acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by aristolochic acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen-positive cells and total aristolochic acid-DNA adducts were significantly reduced in mice receiving aristolochic acid plus probenecid compared with mice treated with aristolochic acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of aristolochic acid nephropathy.


Assuntos
Ácidos Aristolóquicos , Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/efeitos dos fármacos , Nefrite Intersticial/prevenção & controle , Probenecid/farmacologia , Substâncias Protetoras/farmacologia , Animais , Atrofia , Biomarcadores/sangue , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Creatinina/sangue , Citoproteção , Adutos de DNA/metabolismo , Modelos Animais de Doenças , Fibrose , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Túbulos Renais/metabolismo , Túbulos Renais/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nefrite Intersticial/sangue , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/patologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fatores de Tempo
13.
Eur J Pharmacol ; 683(1-3): 294-300, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22449377

RESUMO

In addition to antiasthmatic effect, the cysteinyl leukotriene receptor 1 (CysLT1) antagonist montelukast shows renoprotective effect during ischemia/reperfusion and cyclosporine-induced renal damage. Here, we proposed that montelukast protects against rhabdomyolysis-induced acute renal failure. Compared with saline-treated rats, at 48 h following the induction of rhabdomyolysis using intramuscular glycerol (10 ml 50% glycerol/kg), significant elevations in serum levels of urea, creatinine, phosphate and acute renal tubular necrosis were observed. This was associated with elevations in serum Fas, interleukin-10, tumor necrotic factor-alpha, and transforming growth factor-beta1 and renal malondialdehyde and nitrite and detrimental reductions in renal catalase and superoxide dismutase activities. The effects of rhabdomyolysis on renal functional, biochemical and structural integrity and the associated changes in cytokines and Fas levels were abolished upon concurrent administration of montelukast (10 mg/kg i.p.) for 3 days (1 day before and 2 days after induction of rhabdomyolysis). Alternatively, administration of the anti-oxidant, α-tocopherol (400 mg/kg i.m.) for 3 days, succeeded in alleviating renal oxidative stress, but had no significant effect on the circulating levels of most cytokines and partially restored kidney functional and structural damage. Serum level of interleukin-6 was not altered by rhabdomyolysis but showed significant elevations in rats treated with montelukast or α-tocopherol. Collectively, motelukast abrogated functional and structural renal damage induced by rhabdomyolysis via ameliorating renal oxidative stress and modulation of systemic cytokines and apoptotic factors production. The results of this work are expected to open new avenues for early prevention of rhabdomyolysis-induced acute renal failure using selective CysLT1 antagonists such as montelukast.


Assuntos
Acetatos/uso terapêutico , Citocinas/sangue , Proteína de Domínio de Morte Associada a Fas/sangue , Necrose Tubular Aguda/prevenção & controle , Antagonistas de Leucotrienos/uso terapêutico , Oxirredutases/metabolismo , Quinolinas/uso terapêutico , Rabdomiólise/fisiopatologia , Animais , Antiasmáticos/uso terapêutico , Antioxidantes/uso terapêutico , Ciclopropanos , Glicerol , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Necrose Tubular Aguda/etiologia , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/fisiopatologia , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores de Leucotrienos/química , Receptores de Leucotrienos/metabolismo , Rabdomiólise/induzido quimicamente , Sulfetos , alfa-Tocoferol/uso terapêutico
14.
Clin Exp Nephrol ; 16(5): 679-89, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22398959

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a critical condition for kidney and other remote organs, including the lung. However, available treatments for AKI are limited. In this study, we explored the effect of adipose-derived mesenchymal cells on a mouse model of AKI. METHODS: Adipose-derived mesenchymal cells were isolated from mouse subcutaneous and peritoneal adipose tissue by digestion with collagenase type I. The left renal artery and vein of C57BL/6 mice were clamped for 45 min to induce ischemia and were injected with the adipose-derived mesenchymal cells [1 × 10(5) cells/0.2 ml phosphate-buffered saline (PBS)] or 0.2 ml PBS via the tail vein on days 0, 1, and 2. RESULTS: The adipose-derived mesenchymal cells had stem-cell surface markers and multilineage differentiating potentials. Administered adipose-derived mesenchymal cells homed primarily into lung. Interestingly, repeated administration of adipose-derived mesenchymal cells reduced acute tubular necrosis and interstitial macrophage infiltration in the injured kidney, accompanied with reduced cytokine and chemokine expression. CONCLUSION: Adipose-derived mesenchymal cells can be used as cell-based therapy for ischemic kidney injury.


Assuntos
Injúria Renal Aguda/terapia , Transplante de Células-Tronco Mesenquimais , Traumatismo por Reperfusão/terapia , Injúria Renal Aguda/patologia , Tecido Adiposo/citologia , Animais , Diferenciação Celular , Separação Celular , Quimiocinas/biossíntese , Citocinas/biossíntese , Rim/patologia , Necrose Tubular Aguda/prevenção & controle , Pulmão/patologia , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/patologia
15.
Kidney Int ; 81(7): 662-73, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22258319

RESUMO

Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3ß inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3ß targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3ß inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3ß, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3ß activity and prevented GSK3ß-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3ß abolished the effects of TDZD-8. Hence, inhibition of GSK3ß ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.


Assuntos
Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/fisiopatologia , Anti-Inflamatórios não Esteroides/toxicidade , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Trifosfato de Adenosina/biossíntese , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/deficiência , Ciclo-Oxigenase 2/genética , Peptidil-Prolil Isomerase F , Ciclofilinas/metabolismo , Diclofenaco/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Glicogênio Sintase Quinase 3 beta , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/fisiopatologia , Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Necrose , Oxirredução , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tiadiazóis/farmacologia
16.
Ren Fail ; 34(3): 350-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22260331

RESUMO

BACKGROUND: Acute tubular necrosis (ATN) is the most common reason for acute kidney injury (AKI), and there is still an absence of effective therapies. OBJECTIVE: To assess the value of bone marrow cell mobilization by stem cell factor (SCF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy in rats with gentamicin-induced ATN. METHODS: ATN was induced in male Sprague-Dawley (SD) rats with five daily high-dose intraperitoneal injections of gentamicin. Subcutaneous injections of SCF and GM-CSF were administered simultaneously and these cytokines were observed on days 2, 5, 10, 17, 24, and 31. Peripheral blood and renal tissue CD34+ cell count, mortality rate, blood urea nitrogen (BUN), serum creatinine (SCr), creatinine clearance rate (CCr), and histopathologic lesion scores were determined. Twelve hours after bone marrow ablation (BMA) by lethal X-ray radiation, specific pathogen-free (SPF) ATN rats were given five daily injections of SCF and GM-CSF. BUN, SCr, and histopathologic lesion scores were evaluated on days 2, 5, and 10. RESULTS: Peripheral blood CD34+ cell count increased significantly in ATN rats between 2 and 10 days after SCF and GM-CSF injection. Mortality was reduced from 34.7% in the ATN group to 18.6% in the ATN+CSF. In addition, cytokines administration significantly decreased SCr and BUN. Moreover, cytokines rapidly ameliorated tubular injury. There was no significant effect on ATN rats after BMA. CONCLUSIONS: This study demonstrated that SCF and GM-CSF effectively mobilized bone marrow cells in ATN rats, and cytokines administration partially prevented gentamicin-induced ATN. These results suggest that bone marrow stem cell (BMSC) mobilization may be an effective therapy for ATN.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/fisiologia , Recuperação de Função Fisiológica , Fator de Células-Tronco/farmacologia , Animais , Creatinina/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Necrose Tubular Aguda/metabolismo , Necrose Tubular Aguda/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
17.
Clin Exp Immunol ; 167(1): 169-77, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22132896

RESUMO

Reperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia-reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twenty-four hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury.


Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Pré-Medicação , Traumatismo por Reperfusão/prevenção & controle , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Complemento C3/análise , Creatinina/sangue , Citocinas/sangue , Avaliação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Imunossupressores/uso terapêutico , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/etiologia , Necrose Tubular Aguda/imunologia , Necrose Tubular Aguda/prevenção & controle , Masculino , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/imunologia , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico
18.
Tissue Cell ; 43(6): 392-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22000907

RESUMO

The present investigation reports the effect of rosmarinic acid (RA), an antioxidant on gentamicin sulphate (GS)-induced renal oxidative damage in rats. Rosmarinic acid (RA) has been demonstrated to have antioxidant, free radical scavenger and anti-inflammatory effects. Twenty-eight Sprague-Dawley rats were divided in to four equal groups as follows: group 1 (control), group 2 (GS 100 mg/kg/d ip), group 3 (GS 100 mg/kg/d ip+RA 50 mg/kg/d) and group 4 (GS 100 mg/kg/d ip+RA 100 mg/kg/d). Treatments were administrated once daily for 12 days. After 12 days 24h urine was collected, blood was sampled and kidneys were removed. Serum and kidney tissue MDA assessed by thiobarbituric acid. Kidney paraffin sections (5 µm thickness) from the left kidney stained with periodic acid Schiff. Tubular necrosis was studied semiquantitatively and glomerular volume and volume density of proximal convoluted tubule (PCT) estimated stereologically. Kidney homogenize were prepared from right kidney. Serum creatinine, urea and kidney antioxidant enzymes activity were assessed by special kits. Data were compared by SPSS 13 software and Mann-Whitney test at p < 0.05. Co treatment of GS and RA (High dose) significantly decreased serum creatinine, MDA, urea, tubular necrosis (p < 0.05) and increase renal GSH, GPX, CAT, SOD, volume density of PCT and creatinine clearance significantly in comparison with GS group (p < 0.05). Treatment with RA (high dose) maintained serum creatinine, volume density of PCT, renal GSH, GPX, SOD and MDA as the same level as control group significantly (p < 0.05). In conclusion, RA alleviates GS nephrotoxicity via antioxidant activity, increase of renal GSH content and increase of renal antioxidant enzymes activity.


Assuntos
Antioxidantes/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Gentamicinas/antagonistas & inibidores , Necrose Tubular Aguda/prevenção & controle , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Biomarcadores/sangue , Biomarcadores/urina , Creatinina/sangue , Gentamicinas/toxicidade , Glutationa/sangue , Rim/patologia , Necrose Tubular Aguda/induzido quimicamente , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ureia/sangue , Ácido Rosmarínico
19.
Inflammation ; 34(1): 67-71, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20419391

RESUMO

Cisplatin is one of the most active cytotoxic agents in the treatment of cancer, but its clinical use is frequently limited by nephrotoxicity. The study presented here attempted to evaluate the effect of fructose-1,6-bisphosphate in the cisplatin-induced nephrotoxicity in rats. The drugs were administered intraperitoneally as a single dose: sodium chloride 0.9%, cisplatin (6 mg/kg), fructose-1,6-bisphosphate (500 mg/kg), and cisplatin plus fructose-1,6-bisphosphate (6 and 500 mg/kg, respectively). The use of cisplatin resulted in significant elevation of serum creatinine and urea. The group that received cisplatin plus fructose-1,6-bisphosphate presented a significantly lower level of creatinine and urea compared to the cisplatin group. Acute tubular necrosis was demonstrated in the animals that received cisplatin and a less severe one in the cisplatin plus fructose-1,6-bisphosphate group. Fructose-1,6-bisphosphate has a protective effect over renal function and renal parenchyma in a rat experimental model of cisplatin-induced nephrotoxicity. The anti-inflammatory effect of fructose-1,6-bisphosphate confirms its protective effect in cases of cellular injury.


Assuntos
Cisplatino/toxicidade , Frutosedifosfatos/farmacologia , Necrose Tubular Aguda/induzido quimicamente , Rim/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Animais , Creatinina/sangue , Citoproteção , Frutosedifosfatos/administração & dosagem , Rim/patologia , Necrose Tubular Aguda/prevenção & controle , Masculino , Necrose , Óxido Nítrico/sangue , Óxido Nítrico Sintase/genética , Ratos , Ratos Wistar , Ureia/sangue , Redução de Peso/efeitos dos fármacos
20.
Pediatr Res ; 67(3): 257-62, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19915515

RESUMO

Ischemia-reperfusion injury (IRI) is a leading cause of acute tubular necrosis (ATN) and delayed graft function in transplanted organs. Up-regulation of matrix metalloproteinases (MMPs) propagates the microinflammatory response that drives IRI. This study sought to determine the specific effects of Marimastat (Vernalis, BB-2516), a broad spectrum MMP and TNF-alpha-converting enzyme inhibitor, on IRI-induced ATN. Mice were pretreated with Marimastat or methylcellulose vehicle for 4 d before surgery. Renal pedicles were bilaterally occluded for 30 min and allowed to reperfuse for 24 h. Baseline creatinine levels were consistent between experimental groups; however, post-IRI creatinine levels were 4-fold higher in control mice (p < 0.0001). The mean difference between the post-IRI histology grades of Marimastat-treated and control kidneys was 1.57 (p = 0.003), demonstrating more severe damage to control kidneys. Post-IRI mean (+/-SEM) MMP-2 activity rose from baseline levels in control mice (3.62 +/- 0.99); however, pretreated mice presented only a slight increase in mean MMP-2 activity (1.57 +/- 0.72) (p < 0.001). In conclusion, these data demonstrate that MMP inhibition is associated with a reduction of IRI in a murine model.


Assuntos
Ácidos Hidroxâmicos/farmacologia , Necrose Tubular Aguda/prevenção & controle , Rim/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Biomarcadores/sangue , Western Blotting , Creatinina/sangue , Modelos Animais de Doenças , Rim/irrigação sanguínea , Rim/enzimologia , Rim/patologia , Necrose Tubular Aguda/enzimologia , Necrose Tubular Aguda/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Índice de Gravidade de Doença
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