RESUMO
BACKGROUND: Impaired nitric oxide (NO) release in chronic renal failure has been implicated in the pathogenesis of hypertension and the progression of renal insufficiency. We investigated whether gene delivery of the endothelial NO synthase (eNOS) improves NO release and reduces blood pressure and renal failure and injury in rats with reduced renal mass. METHODS: Renal failure was induced by renal artery branches ligation. Two weeks later, rats with renal failure were divided into three groups and received an intravenous injection of the vehicle or the adenovirus that expresses eNOS or ß-galactosidase (ß-gal). Systolic blood pressure, renal parameters and histopathology were assessed at Week 4 after gene delivery. RESULTS: At the end of the study, systolic blood pressures, serum creatinine, proteinuria, urinary endothelin-1 (ET-1) excretion and renal cortex ET-1 levels were increased, whereas plasma and urine NO(2)/NO(3) were reduced in renal failure rats as compared to normal controls. Renal injury comprised blood vessel media hypertrophy, focal and segmental glomerular sclerosis, tubular atrophy and interstitial fibrosis. Gene delivery of eNOS, but not ß-gal, prevented an increase in systolic blood pressure and proteinuria, and a reduction in plasma and urine NO(2)/NO(3). eNOS gene delivery also reduced a rise in serum creatinine, urinary ET-1 excretion and renal cortex ET-1 levels, and the renal vascular, glomerular and tubular injury. CONCLUSION: This study indicates that eNOS gene delivery in rats with renal failure improves NO release, which likely prevents the aggravation of hypertension and slows down the progression of renal failure and injury.
Assuntos
Injúria Renal Aguda/prevenção & controle , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos/uso terapêutico , Hipertensão/terapia , Óxido Nítrico Sintase Tipo III/genética , Insuficiência Renal/prevenção & controle , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Adenoviridae/genética , Animais , Bovinos , Células Cultivadas , Endotelina-1/urina , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Hipertensão/genética , Masculino , Óxido Nítrico/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Insuficiência Renal/genética , beta-Galactosidase/metabolismoRESUMO
OBJECTIVE: We investigate the role of transforming growth factor-beta (TGF-beta) in hypertension and renal failure progression in uremic rats, and whether it modulates the endothelin (ET) system. DESIGN: Following renal mass reduction, uremic rats (Nx) received the pan-specific TGF-beta neutralizing antibody 1D11 (0.5 mg/kg, three times/week), the isotype control antibody 13C4 or the AT1 antagonist losartan (10 mg/kg per day) for 6 weeks. RESULTS: Before treatment, the blood pressure was higher in Nx rats and increased further over time in Nx+13C4 rats. At the end of the study, Nx+13C4 rats exhibited increased serum creatinine, proteinuria and renal expression and excretion of TGF-beta1 and ET-1. ET-1 concentrations were greater in vascular and renal tissues, whereas the ETB receptor expression was reduced. Renal injuries were comprised of blood vessel hypertrophy, glomerular sclerosis, tubular atrophy and interstitial fibrosis, which was associated with increased alpha-smooth muscle actin expression. Treatment of uremic rats with the 1D11 antibody attenuated the increase in blood pressure and the decline in renal function. Losartan normalized the blood pressure and significantly attenuated the increase in serum creatinine and proteinuria. However, both treatments prevented renal TGF-beta1 and ET-1 overexpression, and prevented all renal histological injuries. The 1D11 antibody only improved ETB receptor expression. CONCLUSIONS: Neutralization of TGF-beta attenuates hypertension and renal failure progression in uremic animals, in part, by preventing renal injury processes. These effects may be related to the modulation of the ET system, preventing renal ET-1 overproduction and the reduction of ETB receptor expression. Our data also suggest that TGF-beta1 is involved, at least in part, in the pathological effects related to angiotensin II in chronic renal failure.
Assuntos
Anticorpos/uso terapêutico , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Fator de Crescimento Transformador beta/imunologia , Uremia/complicações , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Anticorpos/imunologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Northern Blotting , Western Blotting , Creatinina/sangue , Endotelina-1/sangue , Endotelina-1/genética , Endotelina-1/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipertensão/complicações , Hipertensão/fisiopatologia , Rim/metabolismo , Rim/patologia , Losartan/administração & dosagem , Losartan/uso terapêutico , Masculino , Testes de Neutralização , Proteinúria/prevenção & controle , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genéticaRESUMO
Information processing limit is a fundamental issue in cognitive psychology. One particular way of studying it is to adopt a temporal span perspective. In this experiment, Weber fractions based on thresholds for duration discrimination are used for adopting this perspective. The results showed that, contrary to the constant predicted by Weber's law, the Weber fraction is larger at 2 than at .2 s. This increase is observed in conditions where inter-trial intervals and cognitive load are manipulated, and is argued to be due to the fact that 2 s is beyond a temporal span limit for processing information.
