RESUMO
BACKGROUND AND AIMS: To evaluate the effects of a high-fat diet during post-weaning growth on intermediate metabolism and retroperitoneal adipose tissue, in adult male rats exposed to adequate or deficient zinc intake during prenatal and postnatal life. METHODS AND RESULTS: Female Wistar rats were fed low- or control-zinc diets from pregnancy to offspring weaning. Male offspring born from control mothers were fed either control or high-fat, control-zinc diets for 60 days. Male offspring born from zinc deficient mothers were fed either low-zinc or high-fat, low-zinc diets for 60 days. At 74 days of life, oral glucose tolerance test was performed. In 81-day-old offspring, blood pressure, lipid profile, plasmatic lipid peroxidation and serum adiponectin level were determined. In retroperitoneal adipose tissue, we evaluated oxidative stress, morphology and adipocytokines mRNA expression. Low-zinc diet induced adipocytes hypertrophy, increased oxidative stress, and decreased adiponectin mRNA expression in adipose tissue. Low-zinc diet increased systolic blood pressure, triglyceridemia, plasmatic lipid peroxidation and glycemia at 3 h after glucose overload. Animals fed high-fat or high-fat, low-zinc diets showed adipocytes hypertrophy, decreased adiponectin mRNA expression, and increased leptin mRNA expression and oxidative stress in adipose tissue. They also exhibited decreased serum adiponectin levels, increased triglyceridemia, plasmatic lipid peroxidation and area under the oral glucose tolerance curve. High-fat, low-zinc diet induced greater alterations in adipocyte hypertrophy, leptin mRNA expression and glucose tolerance test than high-fat diet. CONCLUSION: Zinc deficiency since early stages of intrauterine life could increase susceptibility to metabolic alterations induced by high-fat diets during postnatal life.
Assuntos
Dieta Hiperlipídica , Desnutrição , Gravidez , Ratos , Animais , Masculino , Feminino , Dieta Hiperlipídica/efeitos adversos , Leptina , Ratos Wistar , Adiponectina , Adipócitos/metabolismo , Zinco , Hipertrofia , RNA Mensageiro/metabolismoRESUMO
The aim of this study was to determine whether exogenous administration of C-type natriuretic peptide (CNP) induces functional and morphological vascular changes in spontaneously hypertensive rats (SHR) compared with normotensive rats. Male 12-week-old normotensive Wistar and SHR were administered with saline (NaCl 0.9%) or CNP (0.75 µg/h/100 g) for 14 days (subcutaneous micro-osmotic pumps). Systolic blood pressure (SBP) was measured in awake animals and renal parameters were evaluated. After decapitation, the aorta was removed, and vascular morphology, profibrotic markers, and vascular reactivity were measured. In addition, nitric oxide (NO) system and oxidative stress were evaluated. After 14-days of treatment, CNP effectively reduced SBP in SHR without changes in renal function. CNP attenuated vascular remodeling in hypertensive rats, diminishing both profibrotic and pro-inflammatory cytokines. Also, CNP activated the vascular NO system and exerted an antioxidant effect in aortic tissue of both groups, diminishing superoxide production and thiobarbituric acid-reactive substances, and increasing glutathione content. These results show that chronic treatment with CNP attenuates the vascular damage development in a model of essential hypertension, inducing changes in fibrotic, inflammatory, oxidative, and NO pathways that could contribute to beneficial long-term effects on vascular morphology, extracellular matrix composition, and function. The knowledge of these effects of CNP could lead to improved therapeutic strategies to not only control BP but also reduce vascular damage, primarily responsible for the risk of cardiovascular events.
Assuntos
Aorta/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Natriuréticos/farmacologia , Peptídeo Natriurético Tipo C/farmacologia , Animais , Aorta/metabolismo , Pressão Sanguínea , Citocinas/metabolismo , Glutationa/metabolismo , Rim/efeitos dos fármacos , Masculino , Natriuréticos/administração & dosagem , Natriuréticos/uso terapêutico , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/uso terapêutico , Óxido Nítrico/metabolismo , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Superóxidos/metabolismo , VasoconstriçãoRESUMO
PURPOSE: Zinc restriction during fetal and postnatal development could program cardiovascular diseases in adulthood. The aim of this study was to determine the effects of zinc restriction during fetal life, lactation, and/or post-weaning growth on cardiac inflammation, apoptosis, oxidative stress, and nitric oxide system of male and female adult rats. METHODS: Wistar rats were fed a low- or a control zinc diet during pregnancy and up to weaning. Afterward, offspring were fed either a low- or a control zinc diet until 81 days of life. IL-6 and TNF-α levels, TUNEL assay, TGF-ß1 expression, thiobarbituric acid-reactive substances that determine lipoperoxidation damage, NADPH oxidase-dependent superoxide anion production, antioxidant and nitric oxide synthase activity, mRNA and protein expression of endothelial nitric oxide synthase, and serine1177 phosphorylation isoform were determined in left ventricle. RESULTS: Zinc deficiency activated apoptotic and inflammatory processes and decreased TGF-ß1 expression and nitric oxide synthase activity in cardiac tissue of both sexes. Male zinc-deficient rats showed no changes in endothelial nitric oxide synthase expression, but a lower serine1177 phosphorylation. Zinc deficiency induced an increase in antioxidant enzymes activity and no differences in lipoperoxidation products levels in males. Females were less sensitive to this deficiency exhibiting lower increase in apoptosis, lower decrease in expression of TGF-ß1, and higher antioxidant and nitric oxide enzymes activities. A zinc-adequate diet during postnatal life reversed most of these mechanisms. CONCLUSION: Prenatal and postnatal zinc deficiency induces alterations in cardiac apoptotic, inflammatory, oxidative, and nitric oxide pathways that could predispose the onset of cardiovascular diseases in adult life.
Assuntos
Deficiências Nutricionais/fisiopatologia , Desenvolvimento Fetal , Lactação , Fenômenos Fisiológicos da Nutrição Materna , Miocardite/etiologia , Estresse Oxidativo , Zinco/deficiência , Animais , Apoptose , Biomarcadores/sangue , Biomarcadores/metabolismo , Vasos Coronários/imunologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Deficiências Nutricionais/imunologia , Deficiências Nutricionais/metabolismo , Deficiências Nutricionais/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Regulação Enzimológica da Expressão Gênica , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Masculino , Miométrio/imunologia , Miométrio/metabolismo , Miométrio/patologia , Miométrio/fisiopatologia , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Gravidez , Distribuição Aleatória , Ratos Wistar , DesmameRESUMO
The aim of this study was to evaluate whether moderate zinc restriction in rats throughout fetal life, lactation, and/or postweaning growth results in early changes in cardiac morphology predisposing the onset of cardiac dysfunction in adult life as well as sex-related differences in the adaptation to this nutritional injury. Female Wistar rats received low or control zinc diets from the beginning of pregnancy up to offspring weaning. After being weaned, offspring were fed either a low or control zinc diet until 81 days. Systolic blood pressure was measured. Echocardiographic and electrocardiographic examinations, morphological experiments, and apoptosis by TUNEL assay were performed in the left ventricle. In the early stages, zinc-deficient male and female offspring showed an increase in cardiomyocyte diameter, probably associated with an increase in cardiac apoptotic cells, but smaller myocyte diameters in adulthood. In adult males, this nutritional injury induced decreased contractility and dilatation of the left ventricle, not allowing the heart to compensate the higher levels of blood pressure, and hypertrophic remodeling of coronary arteries associated with increased blood pressure. Adequate zinc intake during postweaning life did not overcome blood pressure levels but reversed some of the detrimental effects of earlier zinc deficiency in cardiac morphology and function. Females were less sensitive to this deficiency, exhibiting normal levels of blood pressure and no structural or functional heart alterations in adult life. The present study demonstrates that the effects of zinc deficiency on blood pressure, cardiac morphology, and function differ between sexes, with males more predisposed to develop cardiovascular diseases in adulthood.
Assuntos
Vasos Coronários/metabolismo , Dieta , Cardiopatias/etiologia , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Zinco/deficiência , Fatores Etários , Animais , Pressão Sanguínea , Vasos Coronários/patologia , Feminino , Idade Gestacional , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Lactação/metabolismo , Masculino , Miocárdio/patologia , Gravidez , Ratos , Ratos Wistar , Fatores de Risco , Fatores Sexuais , Função Ventricular Esquerda , Aumento de Peso , Zinco/sangueRESUMO
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.
Assuntos
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
This review summarizes the latest findings, from animal models and clinical studies, regarding the cardiovascular and metabolic consequences in adult life of zinc deficiency (ZD) during prenatal and early postnatal life. The effect of zinc supplementation (ZS) and new insights about sex differences in the phenotype and severity of cardiovascular and metabolic alterations are also discussed. Zinc has antioxidant, anti-inflammatory, and antiapoptotic properties and regulates the activity of enzymes involved in regulation of the metabolic, cardiovascular, and renal systems. Maternal ZD is associated with intrauterine growth restriction and low birth weight (LBW). Breast-fed preterm infants are at risk of ZD due to lower zinc uptake during fetal life and reduced gut absorption capacity. ZS is most likely to increase growth in preterm infants and survival in LBW infants in countries where ZD is prevalent. Studies performed in rats revealed that moderate ZD during prenatal and/or early postnatal growth is a risk factor for the development of hypertension, cardiovascular and renal alterations, obesity, and diabetes in adult life. An adequate zinc diet during postweaning life does not always prevent the cardiovascular and metabolic alterations induced by zinc restriction during fetal and lactation periods. Male rats are more susceptible to this injury than females, and some of the mechanisms involved include: 1) alterations in organogenesis, 2) activation of oxidative, apoptotic, and inflammatory processes, 3) dysfunction of nitric oxide and renin-angiotensin-aldosterone systems, 4) changes in glucose and lipid metabolism, and 5) adipose tissue dysfunction. Safeguarding body zinc requirements during pregnancy, lactation, and growth periods could become a new target in the prevention and treatment of cardiovascular and metabolic disorders. Further research is needed to elucidate the efficacy of ZS during early stages of growth to prevent the development of these diseases later in life.
Assuntos
Doenças Cardiovasculares , Desnutrição , Doenças Metabólicas , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/prevenção & controle , Gravidez , Ratos , Ratos Wistar , Vitaminas , ZincoRESUMO
We had previously shown that prenatal exposure to Zn-deficient diets induces an increase in blood pressure and impairs renal function in adult rats. The aim of the present study was to investigate if moderate Zn restriction during early growth periods, fetal life and lactation would induce impairment in the vascular and renal NO system and alterations in plasma lipid profile. We also investigated if these effects persisted into adult life, even when a Zn-replete diet was provided after weaning. Pregnant rats were fed control (30 parts per million (ppm)) or low (8 ppm) Zn diets throughout gestation up to weaning. Afterwards, male offspring from low-Zn mothers were assigned to low- or control-Zn diets during 60 d. Male offspring from control mothers were fed a control diet. Animals exposed to Zn restriction showed low birth weight, increased systolic blood pressure and serum TAG levels, and decreased glomerular filtration rate in adulthood. Zn restriction induced a decrease in vascular and renal NO synthase activity and a reduced expression of the endothelial NO synthase isoform in aorta. A control-Zn diet during post-weaning growth returned TAG levels to normal but was unsuccessful in normalising systolic blood pressure, glomerular filtration rate or NO system activity in Zn-deficient offspring. Zn restriction during fetal life, lactation and/or post-weaning growth induced alterations in the vascular and renal NO system and in lipid metabolism that could contribute to the programming of hypertension and renal dysfunction in adulthood.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal , Zinco/deficiência , Animais , Animais Recém-Nascidos , Peso ao Nascer , Dieta , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Crescimento , Lactação , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Isoformas de Proteínas , Ratos , Ratos Wistar , Triglicerídeos/sangue , Desmame , Zinco/farmacologiaRESUMO
OBJECTIVE: Inflammation and fibrosis are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived factor with a cardiovascular protective role, although its in-vivo effect on cardiac remodeling linked to hypertension has not been investigated. The aim of this study was to determine the effects of chronic administration of CNP on inflammatory and fibrotic cardiac mechanisms in normotensive Wistar rats and spontaneously hypertensive rats (SHR). METHODS: Twelve-week-old male SHR and normotensive rats were infused with CNP (0.75âµg/h/100âg) or isotonic saline (NaCl 0.9%) for 14 days (subcutaneous micro-osmotic pumps). Echocardiograms and electrocardiograms were performed, and SBP was measured. After treatment, transforming growth factor-beta 1, Smad proteins, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, nitric oxide (NO) system and 2-thiobarbituric acid-reactive substances were evaluated in left ventricle. Histological studies were also performed. RESULTS: SHR showed lower cardiac output with signs of fibrosis and hypertrophy in left ventricle, higher NO-system activity and more oxidative damage, as well as higher pro-inflammatory and pro-fibrotic markers than normotensive rats. Chronic CNP treatment-attenuated hypertension and ventricular hypertrophy in SHR, with no changes in normotensive rats. In left ventricle, CNP induced an anti-inflammatory and antifibrotic response, decreasing both pro-fibrotic and pro-inflammatory cytokines in SHR. In addition, CNP reduced oxidative damage as well as collagen content, and upregulated the NO system in both groups. CONCLUSION: Chronic CNP treatment appears to attenuate hypertension and associated end-organ damage in the heart by reducing inflammation and fibrosis.
Assuntos
Coração , Hipertensão , Miocárdio/patologia , Peptídeo Natriurético Tipo C/farmacologia , Animais , Pressão Sanguínea/fisiologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Inflamação , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos WistarRESUMO
This study aimed to evaluate renal morphology and the renal renin-angiotensin system in 6- and 81-day-old male and female offspring exposed to zinc deficiency during fetal life, lactation and/or postnatal growth. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. Afterwards, offspring were fed a low- or a control zinc diet until 81 days of life. In 6- and/or 81-day-old offspring, we evaluated systolic blood pressure, renal morphology, renal angiotensin II and angiotensin 1-7 concentration, and AT1 and AT2 receptors and angiotensin-converting enzymes protein and/or mRNA expression. At 6 days, zinc-deficient male offspring showed decreased glomerular filtration areas, remodelling of renal arteries, greater number of renal apoptotic cells, increased levels of Angiotensin II, higher Angiotensin II/Angiotensin 1-7 ratio and increased angiotensin-converting enzyme 1, AT1 and AT2 receptors mRNA and/or protein expression. Exacerbation of the renal Ang II/AT1 receptor axis and remodelling of renal arteries were also observed in adult zinc-deficient male offspring. An adequate zinc diet during post-weaning life did not improve all the alterations induced by zinc deficiency in early stages of development. Female offspring would appear to be less sensitive to zinc deficiency with no increase in blood pressure or significant alterations in renal morphology and the renin-angiotensin system. Moderate zinc deficiency during critical periods of prenatal and postnatal development leads to early morphological renal alterations and to permanent and long-term changes in the renal renin-angiotensin system that could predispose to renal and cardiovascular diseases in adult life.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Rim/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Sistema Renina-Angiotensina , Zinco/deficiência , Angiotensina II/sangue , Angiotensinas/metabolismo , Animais , Pressão Sanguínea , Dieta , Feminino , Feto/metabolismo , Humanos , Rim/patologia , Lactação/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Caracteres Sexuais , Zinco/administração & dosagemRESUMO
OBJECTIVE: Intrauterine and postnatal micronutrient malnutrition may program metabolic diseases in adulthood. We examined whether moderate zinc restriction in male and female rats throughout fetal life, lactation, or postweaning growth induces alterations in liver, adipose tissue, and intermediate metabolism. METHODS: Female Wistar rats were fed low-zinc or control zinc diets from pregnancy to offspring weaning. After weaning, male and female offspring were fed either a low-zinc or a control zinc diet. At 74 d of life, oral glucose tolerance tests were performed and serum metabolic profiles were evaluated. Systolic blood pressure and oxidative stress and morphology of liver and retroperitoneal adipose tissue were evaluated in 81 d old offspring. RESULTS: Zinc restriction during prenatal and postnatal life induced an increase in systolic blood pressure, hyperglycemia, hypertriglyceridemia, higher serum glucose levels at 180 min after glucose overload, and greater insulin resistance indexes in male rats. Hepatic histologic studies revealed no morphologic alterations, but an increase in lipid peroxidation and catalase activity were identified in zinc-deficient male rats. Adipose tissue from zinc-deficient male rats had adipocyte hypertrophy, an increase in lipid peroxidation, and a reduction in catalase and glutathione peroxidase activity. Adequate dietary zinc content during postweaning growth reversed basal hyperglycemia, hypertriglyceridemia, insulin resistance indexes, hepatic oxidative stress, and adipocyte hypertrophy. Female rats were less sensitive to the metabolic effects of zinc restriction. CONCLUSIONS: This study strengthens the importance of a balanced intake of zinc during growth to ensure adequate lipid and carbohydrate metabolism in adult life.
Assuntos
Exposição Materna/efeitos adversos , Doenças Metabólicas/metabolismo , Complicações na Gravidez/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Zinco/deficiência , Animais , Suplementos Nutricionais , Feminino , Feto/metabolismo , Lactação/metabolismo , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Doenças Metabólicas/etiologia , Gravidez , Complicações na Gravidez/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar , Fatores Sexuais , Desmame , Zinco/administração & dosagemRESUMO
Micronutrient malnutrition during intrauterine and postnatal growth may program cardiovascular diseases in adulthood. We examined whether moderate zinc restriction in male and female rats throughout fetal life, lactation and/or postweaning growth induces alterations that can predispose to the onset of vascular dysfunction in adulthood. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. After weaning, offspring were fed either a low- or a control zinc diet until 81 days. We evaluated systolic blood pressure (SBP), thoracic aorta morphology, nitric oxide (NO) system and vascular reactivity in 6- and/or 81-day-old offspring. At day 6, zinc-deficient male and female offspring showed a decrease in aortic NO synthase (NOS) activity accompanied by an increase in oxidative stress. Zinc-deficient 81-day-old male rats exhibited an increase in collagen deposition in tunica media, as well as lower activity of endothelial NOS (eNOS) that could not be reversed with an adequate zinc diet during postweaning life. Zinc deficiency programmed a reduction in eNOS protein expression and higher SBP only in males. Adult zinc-deficient rats of both sexes showed reduced vasodilator response dependent on eNOS activity and impaired aortic vasoconstrictor response to angiotensin-II associated with alterations in intracellular calcium mobilization. Female rats were less sensitive to the effects of zinc deficiency and exhibited higher eNOS activity and/or expression than males, without alterations in SBP or aortic histology. This work strengthens the importance of a balanced intake of micronutrients during perinatal growth to ensure adequate vascular function in adult life.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Desnutrição/complicações , Fenômenos Fisiológicos da Nutrição Materna , Prenhez , Doenças Vasculares/etiologia , Zinco/deficiência , Acetilcolina/química , Angiotensina II/química , Ração Animal , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Cálcio/metabolismo , Feminino , Lactação , Masculino , Micronutrientes , NG-Nitroarginina Metil Éster/química , Óxido Nítrico/química , Óxido Nítrico Sintase/metabolismo , Nitroprussiato/química , Oxidantes/química , Estresse Oxidativo , Gravidez , Ratos , Ratos Wistar , Sístole , Doenças Vasculares/fisiopatologia , Vasoconstritores/química , Zinco/sangueRESUMO
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.
Assuntos
Rim/crescimento & desenvolvimento , NADPH Desidrogenase/metabolismo , Zinco/deficiência , Animais , Apoptose , Biomarcadores/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Taxa de Filtração Glomerular , Processamento de Imagem Assistida por Computador , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Rim/enzimologia , Rim/patologia , Masculino , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos WistarRESUMO
RESUMEN Introducción: La restricción del crecimiento intrauterino es una alteración del desarrollo fetal que se caracteriza por una tasa de crecimiento durante la etapa fetal que es menor al potencial genético de crecimiento para la edad gestacional. Esta condición plantea una carga importante para la salud pública, ya que aumenta la morbimortalidad de la descendencia, a corto y a largo plazo, particularmente, por asociarse al desarrollo de enfermedad cardiovascular y metabólica en la vida adulta. Objetivos: Mediante el uso de herramientas bioinformáticas nos propusimos identificar posibles genes cardinales involucrados en la restricción del crecimiento intrauterino asociados al desarrollo de obesidad, hipertensión arterial y síndrome metabólico. Material y métodos: Obtuvimos un total de 343 genes involucrados en los fenotipos de interés e identificamos 20 genes que resultaron significativamente relevantes en el análisis de la red de interacción. Particularmente, cuatro de estos genes identificados codifican para factores de crecimiento o sus receptores, VEGFA, PDGFRB, IGF1R y EGFR. Además, identificamos genes relacionados con la insulina y el control de la homeostasis cardiovascular, como son el CTNNB1, APP, MYC y MDMD2. Por otra parte, el análisis de clústeres permitió reconocer los términos de ontología genética más significativos, entre los que se destacan aquellos relacionados con procesos biológicos de proliferación y muerte celular programada, de comunicación intercelular, del metabolismo proteico, y de desarrollo del sistema cardiovascular. Conclusiones: Los genes hallados en este estudio podrían ser de utilidad como biomarcadores putativos de la presencia de alteraciones cardiovasculares y metabólicas asociadas a la restricción del crecimiento intrauterino o potenciales blancos terapéuticos de estrategias de tratamiento orientadas al genotipo del paciente.
ABSTRACT Background: Intrauterine growth restriction is an abnormal fetal development characterized by a fetal growth rate lower than the potential genetic growth for the gestational age. This condition represents a major burden for public health systems, as it increases short and long-term morbidity and mortality in the offspring, particularly because of its association with the development of cardiovascular and metabolic disease in adult life. Objectives: The aim of the present study was to identify possible cardinal genes involved in intrauterine growth restriction associated with the development of obesity, hypertension and metabolic syndrome using bioinformatics tools. Methods: A total of 343 genes involved in the phenotypes of interest were obtained and 20 genes were identified as significantly relevant in the interaction network analysis. Specifically, four of these identified genes encode for growth factors or their receptors, VEGFA, PDGFRB, IGF1R and EGFR. We also identified genes related to insulin and cardiovascular homeostasis as CTNNB1, APP, MYC and MDMD2. Cluster analysis provided the most significant gene ontology terms, including those related to the biological processes of proliferation and programmed cell death, intercellular communication, protein metabolism and development of the cardiovascular system. Conclusions: The genes found in this study could be useful as putative biomarkers for the presence of cardiovascular and metabolic disorders associated with intrauterine growth restriction, or as potential therapeutic targets for treatment strategies directed to the patient's genotype.
RESUMO
OBJECTIVE: The aim of this study was to investigate the effects of chronic treatment with atrial natriuretic peptide (ANP) on renal function, nitric oxide (NO) system, oxidative stress, collagen content and apoptosis in kidneys of spontaneously hypertensive rats (SHR), as well as sex-related differences in the response to the treatment. METHODS: 10 week-old male and female SHR were infused with ANP (100 ng/h/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). Systolic blood pressure (SBP) was recorded and diuresis and natriuresis were determined. After treatment, renal NO synthase (NOS) activity and eNOS expression were evaluated. Thiobarbituric acid-reactive substances (TBARS), glutathione concentration and glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in the kidney. Collagen was identified in renal slices by Sirius red staining and apoptosis by Tunel assay. RESULTS: Female SHR showed lower SBP, oxidative stress, collagen content and apoptosis in kidney, and higher renal NOS activity and eNOS protein content, than males. ANP lowered SBP, increased diuresis, natriuresis, renal NOS activity and eNOS expression in both sexes. Renal response to ANP was more marked in females than in males. In kidney, ANP reduced TBARS, renal collagen content and apoptosis, and increased glutathione concentration and activity of GPx and SOD enzymes in both sexes. CONCLUSIONS: Female SHR exhibited less organ damage than males. Chronic ANP treatment would ameliorate hypertension and end-organ damage in the kidney by reducing oxidative stress, increasing NO-system activity, and diminishing collagen content and apoptosis, in both sexes.
Assuntos
Fator Natriurético Atrial/farmacologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Ratos Endogâmicos SHR , Animais , Apoptose/efeitos dos fármacos , Fator Natriurético Atrial/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Diurese/efeitos dos fármacos , Feminino , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Natriurese/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Fatores SexuaisRESUMO
BACKGROUND: Reduction in renal mass is associated with several structural and functional adaptations including compensatory renal growth and hemodynamic changes. The mediators of the renal hemodynamic adaptations have not been definitively identified. Several investigators have postulated that nitric oxide (NO) is involved this physiological mechanisms. The purpose of this study was to evaluate the role of vascular and renal NO pathway in the model of subtotal nephrectomy-salt load hypertension. MATERIALS AND METHODS: Wistar rats with 75% renal mass reduction (RMR) and saline load were studied during 4 weeks. Weekly, indirect systolic blood pressure (SBP) were measured. One week after nephrectomy, animals were divided in two groups, hypertensive (SBP > 140 mm Hg) and normotensive (SBP < 140 mm Hg). Urinary excretion of nitrates and nitrites (NOx), urinary chemioluminiscence levels and NOS activity in the left kidney and in the thoracic aorta artery were determined at the fourth week after subtotal nephrectomy. RESULTS: Urinary excretion of sodium was higher in normotensive rats than hypertensive rats and in both groups this parameter was higher than in sham rats. NOx excretion and NOS activity in the different nephron segments were higher in normotensive rats than in the hypertensive ones. In contrast, NOS activity in aorta sections and urinary chemiluminescence levels in hypertensive animals were enhanced compared with normotensive rats. These parameters were higher in both groups of nephrectomized rats than in sham ones. CONCLUSION: This study provides evidence to support the fact that the activation of the renal NO system is an important mechanism whereby the remnant kidney regulates sodium and water balance, contributing to control the arterial blood pressure in the renal mass reduction and saline load model.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão Renal/metabolismo , Hipertensão Renal/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Óxido Nítrico/fisiologia , Animais , Modelos Animais de Doenças , Taxa de Filtração Glomerular/fisiologia , Hipertensão Renal/etiologia , Rim/cirurgia , Masculino , Nefrectomia/métodos , Ratos , Ratos Wistar , Solução Salina Hipertônica/efeitos adversosRESUMO
BACKGROUND: A substantial body of epidemiological and experimental evidence suggests that a poor fetal and neonatal environment may "program" susceptibility in the offspring to later development of cardiovascular, renal and metabolic diseases. MATERIALS AND METHODS: This review focuses on current knowledge from the available literature regarding the mechanisms linking an adverse developmental environment with an increased risk for cardiovascular, renal and metabolic diseases in adult life. Moreover, this review highlights important sex-dependent differences in the adaptation to developmental insults. RESULTS: Developmental programming of several diseases is secondary to changes in different mechanisms inducing important alterations in the normal development of several organs that lead to significant changes in birth weight. The different diseases occurring as a consequence of an adverse environment during development are secondary to morphological and functional cardiovascular and renal changes, to epigenetic changes and to an activation of several hormonal and regulatory systems, such as angiotensin II, sympathetic activity, nitric oxide, COX2-derived metabolites, oxidative stress and inflammation. The important sex-dependent differences in the developmental programming of diseases seem to be partly secondary to the effects of sex hormones. Recent studies have shown that the progression of these diseases is accelerated during aging in both sexes. CONCLUSIONS: The cardiovascular, renal and metabolic diseases during adult life that occur as a consequence of several insults during fetal and postnatal periods are secondary to multiple structural and functional changes. Future studies are needed in order to prevent the origin and reduce the incidence and consequences of developmental programmed diseases.
Assuntos
Hipertensão/fisiopatologia , Nefropatias/fisiopatologia , Animais , Peso ao Nascer , Epigênese Genética , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Hipertensão/embriologia , Hipertensão/metabolismo , Nefropatias/embriologia , Nefropatias/metabolismo , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Estresse Oxidativo , Gravidez , Sistema Renina-Angiotensina/fisiologia , Fatores Sexuais , Sistema Nervoso Simpático/embriologia , Sistema Nervoso Simpático/crescimento & desenvolvimento , Sistema Nervoso Simpático/fisiopatologiaRESUMO
INTRODUCTION: The aim of this study was to investigate both the effects of chronic treatment with atrial natriuretic peptide (ANP) on systolic blood pressure (SBP), cardiac nitric oxide (NO) system, oxidative stress, hypertrophy, fibrosis and apoptosis in spontaneously hypertensive rats (SHR), and sex-related differences in the response to the treatment. METHODS: 10 week-old male and female SHR were infused with ANP (100 ng/hr/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). SBP was recorded and nitrites and nitrates excretion (NOx) were determined. After treatment, NO synthase (NOS) activity, eNOS expression, thiobarbituric acid-reactive substances (TBARS) and glutathione concentration were determined in left ventricle, as well as the activity of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD). Morphological studies in left ventricle were performed in slices stained with hematoxylin-eosin or Sirius red to identify collagen as a fibrosis indicator; immunohistochemistry was employed for identification of transforming growth factor beta; and apoptosis was evaluated by Tunel assay. RESULTS: Female SHR showed lower SBP, higher NO-system activity and less oxidative stress, fibrosis and hypertrophy in left ventricle, as well as higher cardiac NOS activity, eNOS protein content and NOx excretion than male SHR. Although ANP treatment lowered blood pressure and increased NOS activity and eNOS expression in both sexes, cardiac NOS response to ANP was more marked in females. In left ventricle, ANP reduced TBARS and increased glutathione concentration and activity of CAT and SOD enzymes in both sexes, as well as GPx activity in males. ANP decreased fibrosis and apoptosis in hearts from male and female SHR but females showed less end-organ damage in heart. Chronic ANP treatment would ameliorate hypertension and end-organ damage in heart by reducing oxidative stress, increasing NO-system activity, and diminishing fibrosis and hypertrophy.
Assuntos
Anti-Hipertensivos/farmacologia , Fator Natriurético Atrial/farmacologia , Hipertensão/fisiopatologia , Animais , Anti-Hipertensivos/administração & dosagem , Apoptose/efeitos dos fármacos , Fator Natriurético Atrial/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Ratos Endogâmicos SHR , Fatores Sexuais , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
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.
Assuntos
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
Micronutrient undernutrition during critical periods of growth has become an important health issue in developing and developed countries, particularly among pregnant women and children having an imbalanced diet. Zinc is a widely studied microelement in infant feeding because it is a component of several enzymes involved in intermediary metabolism ranging from growth to cell differentiation and metabolism of proteins, carbohydrates, and lipids. Human and experimental studies have reported an association between zinc deficiency and the etiopathogenesis of cardiovascular and renal diseases like hypertension, atherosclerosis, congestive heart failure, coronary heart disease, and diabetes. The main links between the development of these pathologies and zinc deficiency are multiple mechanisms involving oxidative stress damage, apoptosis, and inflammation. A substantial body of evidence suggests that a poor in utero environment elicited by maternal dietary or placental insufficiency may "programme" susceptibility in the fetus to later development of cardiovascular, renal, metabolic, and endocrine diseases. Zinc deficiency in rats during intrauterine and postnatal growth can also be considered a model of fetal programming of cardiovascular and renal diseases in adult life. Dietary zinc restriction during fetal life, lactation, and/or postweaning induces an increase in arterial blood pressure and impairs renal function in adult life. This review focuses on the contributions of experimental and clinical studies to current knowledge of the physiologic role of zinc in the cardiovascular and renal systems. Moreover, this review examines the relationship between zinc deficiency during different periods of life and the development of cardiovascular and renal diseases in adult life.
Assuntos
Doenças Cardiovasculares/etiologia , Desenvolvimento Fetal/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição do Lactente , Nefropatias/etiologia , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal , Zinco/deficiência , Animais , Feminino , Humanos , Lactente , GravidezRESUMO
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.