Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
J Am Soc Nephrol ; 29(2): 477-491, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29061652

RESUMO

Progress in research and developing therapeutics to prevent diabetic kidney disease (DKD) is limited by a lack of animal models exhibiting progressive kidney disease. Chronic hypertension, a driving factor of disease progression in human patients, is lacking in most available models of diabetes. We hypothesized that superimposition of hypertension on diabetic mouse models would accelerate DKD. To test this possibility, we induced persistent hypertension in three mouse models of type 1 diabetes and two models of type 2 diabetes by adeno-associated virus delivery of renin (ReninAAV). Compared with LacZAAV-treated counterparts, ReninAAV-treated type 1 diabetic Akita/129 mice exhibited a substantial increase in albumin-to-creatinine ratio (ACR) and serum creatinine level and more severe renal lesions. In type 2 models of diabetes (C57BKLS db/db and BTBR ob/ob mice), compared with LacZAAV, ReninAAV induced significant elevations in ACR and increased the incidence and severity of histopathologic findings, with increased serum creatinine detected only in the ReninAAV-treated db/db mice. The uninephrectomized ReninAAV db/db model was the most progressive model examined and further characterized. In this model, separate treatment of hyperglycemia with rosiglitazone or hypertension with lisinopril partially reduced ACR, consistent with independent contributions of these disorders to renal disease. Microarray analysis and comparison with human DKD showed common pathways affected in human disease and this model. These results identify novel models of progressive DKD that provide researchers with a facile and reliable method to study disease pathogenesis and support the development of therapeutics.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Modelos Animais de Doenças , Hipertensão/complicações , Renina/genética , Animais , Anti-Hipertensivos/uso terapêutico , Creatinina/sangue , Dependovirus , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Progressão da Doença , Feminino , Vetores Genéticos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Hipoglicemiantes/uso terapêutico , Janus Quinases/metabolismo , Óperon Lac/genética , Lisinopril/uso terapêutico , Masculino , Camundongos , Nefrectomia , Óxido Nítrico Sintase Tipo III/genética , Rosiglitazona/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais
2.
Toxicol Pathol ; 46(8): 970-975, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213245

RESUMO

Diabetes mellitus (types 1 and 2) is the leading cause of glomerular disease and end-stage renal disease in most developed countries, with estimates that one-third of people living with diabetes will develop diabetic kidney disease (DKD). The current standard of care medications slow but do not arrest progression of kidney disease, and therefore, therapy for DKD is a highly unmet medical need for patients. To discover and test novel and durable new therapies, it is necessary to develop animal models of human DKD, which authentically recapitulate the human disease state and provide translatable efficacy to human patients. Here, we review selected mouse models of human DKD, which demonstrate many of the features of type 2 human DKD.


Assuntos
Nefropatias Diabéticas , Modelos Animais de Doenças , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Humanos , Camundongos
3.
Toxicol Pathol ; 46(8): 991-998, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30392455

RESUMO

The ReninAAV db/db uNx model of diabetic kidney disease (DKD) exhibits hallmarks of advanced human disease, including progressive elevations in albuminuria and serum creatinine, loss of glomerular filtration rate, and pathological changes. Microarray analysis of renal transcriptome changes were more similar to human DKD when compared to db/db eNOS-/- model. The model responds to treatment with arterial pressure lowering (lisinopril) or glycemic control (rosiglitazone) at early stages of disease. We hypothesized the ReninAAV db/db uNx model with advanced disease would have residual disease after treatment with lisinopril, rosiglitazone, or combination of both. To test this, ReninAAV db/db uNx mice with advanced disease were treated with lisinopril, rosiglitazone, or combination of both for 10 weeks. All treatment groups showed significant lowering of urinary albumin to creatinine ratio compared to baseline; however, only combination group exhibited lowering of serum creatinine. Treatment improved renal pathological scores compared to baseline values with residual disease evident in all treatment groups when compared to db/m controls. Gene expression analysis by TaqMan supported pathological changes with increased fibrotic and inflammatory markers. The results further validate this model of DKD in which residual disease is present when treated with agents to lower arterial pressure and glycemic control.


Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Animais , Humanos , Camundongos , Camundongos Endogâmicos , Transcriptoma
4.
Am J Physiol Renal Physiol ; 312(6): F951-F962, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28249836

RESUMO

Transforming growth factor-alpha (TGFA) has been shown to play a role in experimental chronic kidney disease associated with nephron reduction, while its role in diabetic kidney disease (DKD) is unknown. We show here that intrarenal TGFA mRNA expression, as well as urine and serum TGFA, are increased in human DKD. We used a TGFA neutralizing antibody to determine the role of TGFA in two models of renal disease, the remnant surgical reduction model and the uninephrectomized (uniNx) db/db DKD model. In addition, the contribution of TGFA to DKD progression was examined using an adeno-associated virus approach to increase circulating TGFA in experimental DKD. In vivo blockade of TGFA attenuated kidney disease progression in both nondiabetic 129S6 nephron reduction and Type 2 diabetic uniNx db/db models, whereas overexpression of TGFA in uniNx db/db model accelerated renal disease. Therapeutic activity of the TGFA antibody was enhanced with renin angiotensin system inhibition with further improvement in renal parameters. These findings suggest a pathologic contribution of TGFA in DKD and support the possibility that therapeutic administration of neutralizing antibodies could provide a novel treatment for the disease.


Assuntos
Nefropatias Diabéticas/metabolismo , Rim/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Idoso , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Pressão Sanguínea , Células Cultivadas , Dependovirus/genética , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Receptores ErbB/metabolismo , Matriz Extracelular/metabolismo , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Rim/cirurgia , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Pessoa de Meia-Idade , Nefrectomia , Fosforilação , Sistema Renina-Angiotensina , Transdução de Sinais , Fatores de Tempo , Fator de Crescimento Transformador alfa/antagonistas & inibidores , Fator de Crescimento Transformador alfa/deficiência , Fator de Crescimento Transformador alfa/genética
5.
Toxicol Pathol ; 37(5): 617-28, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19549929

RESUMO

Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure-activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.


Assuntos
Descoberta de Drogas/métodos , Cardiopatias/sangue , Cardiopatias/induzido quimicamente , Isoproterenol/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Troponina I/sangue , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Cardiotônicos/toxicidade , Creatina Quinase/antagonistas & inibidores , Creatina Quinase/sangue , Relação Dose-Resposta a Droga , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Ventrículos do Coração/efeitos dos fármacos , Histocitoquímica , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Miocárdio/metabolismo , Miocárdio/patologia , Necrose
6.
Vet Clin North Am Exot Anim Pract ; 12(1): 39-50, v-vi, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19131029

RESUMO

The class Amphibia includes three orders of amphibians: the anurans (frogs and toads), urodeles (salamanders, axolotls, and newts), and caecilians. The diversity of lifestyles across these three orders has accompanying differences in the cardiovascular anatomy and physiology allowing for adaptations to aquatic or terrestrial habitats, pulmonic or gill respiration, hibernation, and body elongation (in the caecilian). This article provides a review of amphibian cardiovascular anatomy and physiology with discussion of unique species adaptations. In addition, amphibians as cardiovascular animal models and commonly encountered natural diseases are covered.


Assuntos
Anfíbios/fisiologia , Doenças Cardiovasculares/veterinária , Fenômenos Fisiológicos Cardiovasculares , Coração/fisiologia , Adaptação Fisiológica , Anfíbios/anatomia & histologia , Animais , Coração/anatomia & histologia , Estágios do Ciclo de Vida/fisiologia , Especificidade da Espécie
7.
J Vet Diagn Invest ; 16(3): 186-90, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15152831

RESUMO

West Nile virus (WNV) infection was diagnosed in 13 gray squirrels (Sciurus carolinensis) and 3 fox squirrels (Sciurus niger) that were observed with neurologic signs before death or found dead. All 16 had gliosis throughout all sections of the brain. Most had lymphoplasmacytic encephalitis or meningoencephalitis, many with admixed neutrophils. Neuronal necrosis and neuronophagia were also prominent features. West Nile virus antigen was demonstrated in the brain, spleen, heart or kidney in 10 of 13 gray squirrels and 3 of 3 fox squirrels by immunohistochemistry. Nucleic acid amplification tests (NAATs) confirmed the presence of WNV in the brain or spinal cord of 10/10 gray squirrels and 1/3 fox squirrels tested. Viral levels were quantified in various tissues of selected gray squirrels, and titers were highest in spleen and brain, with no virus detected in serum. This is the first description of lesions associated with WNV infection in gray and fox squirrels.


Assuntos
Doenças dos Roedores/virologia , Sciuridae , Febre do Nilo Ocidental/veterinária , Vírus do Nilo Ocidental/isolamento & purificação , Animais , Encéfalo/virologia , Feminino , Illinois/epidemiologia , Imuno-Histoquímica/veterinária , Masculino , Neurônios/virologia , RNA Viral/química , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Doenças dos Roedores/epidemiologia , Febre do Nilo Ocidental/epidemiologia , Febre do Nilo Ocidental/patologia , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética
8.
PLoS One ; 9(4): e93297, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24695114

RESUMO

BACKGROUND: Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of the kidney excretory function and is strongly associated with increased early and long-term patient morbidity and mortality. Early diagnosis of AKI is challenging; therefore we profiled plasma microRNA in an effort to identify potential diagnostic circulating markers of renal failure. The goal of the present study was to investigate the dynamic relationship of circulating and renal microRNA profiles within the first 24 hours after bilateral ischemia-reperfusion kidney injury in mice. METHODOLOGY/PRINCIPAL FINDINGS: Bilateral renal ischemia was induced in C57Bl/6 mice (n = 10 per group) by clamping the renal pedicle for 27 min. Ischemia-reperfusion caused highly reproducible, progressive, concordant elevation of miR-714, miR-1188, miR-1897-3p, miR-877*, and miR-1224 in plasma and kidneys at 3, 6 and 24 hours after acute kidney injury compared to the sham-operated mice (n = 5). These dynamics correlated with histologic findings of kidney injury and with a conventional plasma marker of renal dysfunction (creatinine). Pathway analysis revealed close association between miR-1897-3p and Nucks1 gene expression, which putative downstream targets include genes linked to renal injury, inflammation and apoptosis. CONCLUSIONS/SIGNIFICANCE: Systematic profiling of renal and plasma microRNAs in the early stages of experimental AKI provides the first step in advancing circulating microRNAs to the level of promising novel biomarkers.


Assuntos
Injúria Renal Aguda/metabolismo , Isquemia/metabolismo , Rim/metabolismo , MicroRNAs/metabolismo , Plasma/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Biomarcadores/metabolismo , Creatinina/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Reperfusão/métodos
9.
J Nutr ; 135(12 Suppl): 2972S-2977S, 2005 12.
Artigo em Inglês | MEDLINE | ID: mdl-16317157

RESUMO

The association between cruciferous vegetables and cancer prevention has been linked to glucosinolate derivatives. These phytochemicals enhance endogenous detoxification, leading to inactivation of potential carcinogens before initiation occurs. Two derivatives, indole-3-carbinol (I3C) and 1-cyano-2-hydroxy-3-butene (crambene) were shown in rats to induce a synergistic enhancement of detoxification enzyme activity. To follow up on these findings, a short-term carcinogenicity study using aflatoxin B1 (AFB(1)) was performed in which male F344 rats were fed diets supplemented with these 2 compounds alone or in combination. Groups included a negative control group (no AFB(1), crambene, or I3C), a crambene group (diet 0.150% crambene), an I3C group (diet 0.165% I3C), a high-dose group (diet 0.150% crambene, 0.165% I3C) a low-dose group (diet 0.030% crambene, 0.033% I3C), and a positive control group (AFB(1) treatment only). AFB(1) was administered after 2 wk of dietary pretreatment. Liver sections were scored for lesions including karyomegaly, apoptosis, and biliary hyperplasia and evaluated for expression of the preneoplastic marker glutathione S-transferase-pi (GSTP). I3C and crambene groups were protected against AFB(1) toxicity whereas the low-dose group was not. The high-dose group had scores close to those of the negative controls. For log(10) transformed 2- and 3-dimensional GSTP data, the high-dose group demonstrated synergistic reduction in GSTP-positive area and an additive reduction in GSTP-positive volume compared with the crambene and I3C groups. The low-dose group had no effect. In conclusion, high combination dietary doses of I3C and crambene demonstrated enhanced protection from AFB(1). Low combination doses, as might be realistically in the diet, were not effective.


Assuntos
Alcenos/uso terapêutico , Antioxidantes/uso terapêutico , Dieta , Indóis/uso terapêutico , Neoplasias Experimentais/prevenção & controle , Nitrilas/uso terapêutico , Aflatoxina B1/antagonistas & inibidores , Aflatoxina B1/toxicidade , Alcenos/administração & dosagem , Alcenos/isolamento & purificação , Animais , Antioxidantes/administração & dosagem , Brassicaceae , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Indóis/isolamento & purificação , Fígado/patologia , Masculino , Neoplasias Experimentais/induzido quimicamente , Nitrilas/administração & dosagem , Nitrilas/isolamento & purificação , Preparações de Plantas/uso terapêutico , Ratos , Ratos Endogâmicos F344
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA