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BACKGROUND AND PURPOSE: The AT2 receptor plays a role in metabolism by opposing the actions triggered by the AT1 receptors. Activation of AT2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT2 receptors activation improves metabolism in diabetic mice. EXPERIMENTAL APPROACH: Female diabetic (db/db) and non-diabetic (db/+) mice were treated for 1 month with the selective AT2 agonist, compound 21 (C21, 0.3 mg·kg-1 ·day-1 , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub-pressor dose of the NOS inhibitor l-NAME (0.1 mg·ml-1 , drinking water). KEY RESULTS: C21-treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline-treated db/db mice. Also, C21-treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline-treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21-treated db/db mice compared with saline-treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l-NAME. CONCLUSION AND IMPLICATIONS: Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Receptor Tipo 2 de AngiotensinaRESUMO
OBJECTIVE: Fetal and postnatal zinc deficiencies induce an increase in arterial blood pressure and impair renal function in male adult rats. We therefore hypothesized that these renal alterations are present in early stages of life and that there are sexual differences in the adaptations to this nutritional injury. The aim was to study the effects of moderate zinc deficiency during fetal life and lactation on renal morphology, oxidative stress, apoptosis, and the nitric oxide system in male and female rats at 21 d of life. METHODS: Female Wistar rats received low (8 ppm) or control (30 ppm) zinc diets from the beginning of pregnancy to weaning. Glomerulus number, morphology, oxidative stress, apoptotic cells, nitric oxide synthase activity, and protein expression were evaluated in the kidneys of offspring at 21 d. RESULTS: Zinc deficiency decreased the nephron number, induced glomerular hypertrophy, increased oxidative damage, and decreased nitric oxide synthase activity in the male and female rat kidneys. Nitric oxide synthase activity was not affected by inhibitors of the neuronal or inducible isoforms, so nitric oxide was mainly generated by the endothelial isoenzyme. Gender differences were observed in glomerular areas and antioxidant enzyme activities. CONCLUSION: Zinc deficiency during fetal life and lactation induces an early decrease in renal functional units, associated with a decrease in nitric oxide activity and an increase in oxidative stress, which would contribute to increased arterial blood pressure and renal dysfunction in adulthood. The sexual differences observed in this model may explain the dissimilar development of hypertension and renal diseases in adult life.
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Rim/patologia , Rim/fisiopatologia , Óxido Nítrico/metabolismo , Zinco/deficiência , Animais , Apoptose , Dieta , Feminino , Hipertensão/etiologia , Nefropatias/etiologia , Lactação , Masculino , Troca Materno-Fetal , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Fatores Sexuais , Zinco/administração & dosagemRESUMO
Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng·kg(-1)·min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy.
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Angiotensina I/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Proteinúria/tratamento farmacológico , Proteínas de Fase Aguda/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Fibrose , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Rim/patologia , Lipocalina-2 , Lipocalinas/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proteinúria/metabolismo , Proteinúria/patologia , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Zucker , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Introducción Numerosos estudios sugieren que trastornos metabólicos y desequilibrios nutricionales durante la vida intrauterina pueden inducir adaptaciones que programen enfermedades cardiovasculares e hipertensión arterial. En trabajos previos mostramos que la restricción moderada de cinc durante la vida fetal, la lactancia y/o el crecimiento conduce al desarrollo de hipertensión arterial y disfunción renal en la adultez. Objetivos Evaluar la presencia de alteraciones cardiovasculares tempranas en ratas sometidas a una deficiencia moderada de cinc durante la vida fetal y la lactancia y si existen diferencias respecto del sexo. Material y métodos Ratas Wistar hembras recibieron durante la preñez hasta el destete una dieta control o baja en cinc. En el momento del nacimiento se conformaron cuatro grupos experimentales: machos y hembras nacidos de madres bajas y machos y hembras nacidos de madres controles. A los 6 y a los 21 días de vida se sacrificaron y se determinaron el peso corporal, el peso del corazón, parámetros morfométricos cardiovasculares, la actividad de la óxido nítrico sintasa en el sistema cardiovascular y el estado oxidativo cardíaco. Resultados El aporte insuficiente de cinc durante la vida fetal y la lactancia indujo un proceso de remodelación del cardiomiocito, diferente en machos que en hembras, un aumento del estrés oxidativo cardíaco, una remodelación hipotrófica de la aorta torácica y una disminución de la actividad de la óxido nítrico sintasa en el sistema cardiovascular. Conclusiones Este trabajo demuestra que la deficiencia de cinc induce alteraciones cardiovasculares, distintas en machos que en hembras, tempranas en el desarrollo, que podrían contribuir a la programación de enfermedades en la vida adulta.
Background Several studies suggest that metabolic disorders and nutrition imbalance during prenatal life may induce adaptations that program cardiovascular diseases and hypertension. We have previously shown that moderate zinc restriction during prenatal life, lactation and/or growth leads to the development of hypertension and renal dysfunction in adulthood. Objectives To evaluate the presence of early cardiovascular alterations in rats exposed to a moderate zinc deficient diet during prenatal life and lactation, and to determine whether there are differences between males and females. Material and Methods Female Wistar rats received low zinc diet or control diet from the beginning of pregnancy up to weaning. Four experimental groups were established at birth: males and females born from low-diet mothers, and males and females born from control-diet mothers. Male and female offspring were sacrificed at 6 and 21 days of life to evaluate body weight, heart weight, cardiovascular morphometric parameters and nitric oxide synthase activity in the cardiovascular system and cardiac oxidative status. Results The insufficient zinc intake during prenatal life and lacta-tion induced a remodeling process of the cardiomyocyte which was different in males and females, increased cardiac oxidative stress, produced a hypotrophic remodeling of the thoracic aorta and reduced nitric oxide synthase activity in the cardiovascular system. Conclusions This study shows that zinc deficiency induces cardiovascular abnormalities in early stages of development, which are different in males and females that may contribute to programming of diseases in adulthood.
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The present study examined whether chronic treatment with angiotensin (ANG)-(1-7) reduces cardiac remodeling and inhibits growth-promoting signaling pathways in the heart of fructose-fed rats (FFR), an animal model of insulin resistance. Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of the corresponding diet, control and FFR were implanted with osmotic pumps that delivered ANG-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We determined heart weight, myocyte diameter, interstitial fibrosis, and perivascular collagen type III deposition as well as the phosphorylation degree of ERK1/2, JNK1/2, and p38MAPK. FFR showed a mild hypertension that was significantly reduced after ANG-(1-7) treatment. Also, FFR displayed higher ANG II circulating and local levels in the heart that remained unaltered after chronic ANG-(1-7) infusion. An increased heart-to-body weight ratio, myocyte diameter, as well as left ventricular fibrosis and perivascular collagen type III deposition were detected in the heart of FFR. Interestingly, significant improvements in these cardiac alterations were obtained after ANG-(1-7) treatment. Finally, FFR that received ANG-(1-7) chronically displayed significantly lower phosphorylation levels of ERK1/2, JNK1/2, and p38MAPK. The beneficial effects obtained by ANG-(1-7) were associated with normal values of Src-homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity in the heart. In conclusion, chronic ANG-(1-7) treatment ameliorated cardiac hypertrophy and fibrosis and attenuated the growth-promoting pathways in the heart. These findings show an important protective role of ANG-(1-7) in the heart of insulin-resistant rats.
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Angiotensina I/farmacologia , Frutose/efeitos adversos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Resistência à Insulina , Fragmentos de Peptídeos/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/fisiologia , Carboidratos da Dieta/efeitos adversos , Modelos Animais de Doenças , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Insulina/sangue , Masculino , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Intrauterine and postnatal zinc restriction may result in an adverse environment for the development of cardiovascular and renal systems. This study evaluated the effects of moderate zinc deficiency during fetal life, lactation, and/or postweaning growth on systolic blood pressure, renal function, and morphology in adult life. Female Wistar rats received low (8 ppm) or control (30 ppm) zinc diets from the beginning of pregnancy up to weaning. After weaning, male offspring of each group of mothers were fed low or control zinc diet. Systolic blood pressure, creatinine clearance, proteinuria, renal morphology, renal apoptosis. and renal oxidative stress state were evaluated after 60 days. Zinc deficiency during pre- and postweaning growth induced an increase in systolic blood pressure and a decrease in the glomerular filtration rate associated with a reduction in the number and size of nephrons. Activation of renal apoptosis, reduction in catalase activity, glutathione peroxidase activity, and glutathione levels and increase in lipid peroxidation end products could explain these morphometric changes. Zinc deficiency through pre- and postweaning growth induced more pronounced renal alteration than postweaning zinc deficiency. These animals showed signs of renal fibrosis, proteinuria, increased renal apoptosis, and higher lipid peroxidation end products. A control diet during postweaning growth did not totally overcome renal oxidative stress damage, apoptosis, and fibrosis induced by zinc deficiency before weaning. In conclusion, zinc deficiency during a critical period of renal development and maturation could induce functional and morphological alterations that result in elevated blood pressure and renal dysfunction in adult life.
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Fenômenos Fisiológicos da Nutrição Animal , Pressão Sanguínea , Rim/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Efeitos Tardios da Exposição Pré-Natal , Proteinúria/fisiopatologia , Zinco/deficiência , Animais , Apoptose , Catalase/metabolismo , Creatinina/metabolismo , Feminino , Fibrose , Taxa de Filtração Glomerular , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Rim/enzimologia , Rim/crescimento & desenvolvimento , Rim/patologia , Lactação , Peroxidação de Lipídeos , Masculino , Tamanho do Órgão , Estresse Oxidativo , Gravidez , Proteinúria/metabolismo , Proteinúria/patologia , Ratos , Ratos Wistar , Superóxido Dismutase , Fatores de Tempo , DesmameRESUMO
This study was designed to investigate the effects of moderate zinc deficiency during growth on renal morphology and function in adult life. Weaned male Wistar rats were divided into two groups and fed either a moderately zinc-deficient diet (zinc: 8 mg/kg, n=12) or a control diet (zinc: 30 mg/kg, n=12) for 60 days. We evaluated: renal parameters, NADPH-diaphorase and nitric oxide synthase activity in kidney, renal morphology and apoptotic cells in renal cortex. Zinc-deficient rats showed a decrease in glomerular filtration rate and no changes in sodium and potassium urinary excretion. Zinc deficiency decreased NADPH diaphorase activity in glomeruli and tubular segment of nephrons, and reduced activity of nitric oxide synthase in the renal medulla and cortex, showing that zinc plays an important role in preservation of the renal nitric oxide system. A reduction in nephron number, glomerular capillary area and number of glomerular nuclei in cortical and juxtamedullary areas was observed in zinc deficient kidneys. Sirius red staining and immunostaining for alpha-smooth muscle-actin and collagen III showed no signs of fibrosis in the renal cortex and medulla. An increase in the number of apoptotic cells in distal tubules and cortical collecting ducts neighboring glomeruli and, to a lesser extent, in the glomeruli was observed in zinc deficient rats. The major finding of our study is the emergence of moderate zinc deficiency during growth as a potential nutritional factor related to abnormalities in renal morphology and function that facilitates the development of cardiovascular and renal diseases in adult life.