Zinc deficiency and a high-fat diet during growth: Metabolic and adipocyte alterations in rats.

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.

Impact of Zinc Deficiency During Prenatal and/or Postnatal Life on Cardiovascular and Metabolic Diseases: Experimental and Clinical Evidence.

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.

Cardiac morphological and functional changes induced by C-type natriuretic peptide are different in normotensive and spontaneously hypertensive rats.

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 (0.75 µg/h/100 g) 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.

Chronic treatment with atrial natriuretic peptide in spontaneously hypertensive rats: beneficial renal effects and sex differences.

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.

Programación de hipertensión arterial por restricción moderada de cinc durante la vida fetal y la lactancia: Alteraciones morfológicas y funcionales tempranas del sistema cardiovascular en ratas de ambos sexos / Fetal Programming of Hypertension Induced by Moderate Zinc Restriction during Prenatal Life and Lactation: Early Morphological and Functional Alterations in Cardiovascular System in Both Sexes / Fetal Programming of Hypertension induced by Moderate Zinc Restriction during Prenatal Life and Lactation: early Morphological and Functional alterations in cardiovascular system in both sexes

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.

Programación temprana de alteraciones en el sistema del óxido nítrico renal y vascular inducidas por la deficiencia de cinc / Early Programming of Alterations in Renal and Vascular Nitric Oxide System Induced by Zinc-Related Deficiencies

Introducción Numerosos estudios mostraron que la deficiencia nutricional durante la vida fetal y posnatal predisponen al desarrollo de patologías en la vida adulta, como la hipertensión arterial y las enfermedades renales. La distribución ubicua del cinc y sus propiedades químicas determinan su esencialidad en los sistemas biológicos. Objetivos Evaluar si las alteraciones renales y cardiovasculares en la vida adulta inducidas por la restricción moderada de cinc durante la vida fetal, la lactancia y/o el crecimiento se asocian con cambios en el sistema del óxido nítrico. Material y métodos Ratas Wistar hembra recibieron durante la preñez hasta el destete de las crías una dieta control o una baja en cinc. Luego del destete, las crías macho se asignaron al azar a dos grupos que recibieron una dieta control o una baja en cinc durante 60 días. Resultados Los resultados mostraron que el aporte insuficiente de cinc durante el crecimiento previo y/o posterior al destete indujo un aumento de la presión arterial y una disminución del volumen de filtrado glomerular en la vida adulta, asociados con una disminución del sistema del óxido nítrico renal y vascular. Además, el bajo aporte de este mineral durante la vida fetal indujo un peso menor al nacer, que se correlacionó en forma negativa con la presión arterial en la vida adulta. Conclusiones Este trabajo brinda evidencias importantes que sugieren que el aporte inadecuado de cinc durante el crecimiento prenatal y posnatal constituye un factor de riesgo cardiovascular y renal, dado que induce alteraciones en la regulación de la presión arterial y en la función renal en el individuo adulto.

Background Several studies have reported that nutritional deficiencies during fetal and postnatal life predispose to the development of diseases such as hypertension and renal disorders during adulthood. The ubiquitous distribution of zinc and its chemical properties determine their essentiality in the biological systems. Objectives To assess whether renal and cardiovascular alterations induced by moderate zinc restriction during fetal life, lactation period and/or growth are associated with changes in the nitric oxide system. Material and Methods Female Wistar rats received low zinc diet or control diet from the beginning of pregnancy up to weaning. After weaning, male offspring were randomly fed with low zinc diet or control diet for 60 days. Results Zinc deficiency through pre-weaning and post-weaning growth induced increase in blood pressure and reduced glomerular filtration volume in adult life; these findings were associated with reductions in renal and vascular nitric oxide system. In addition, low zinc intake during intrauterine life induced low birth weight offspring which had a negative correlation with blood pressure in adulthood. Conclusions Zinc deficiency during prenatal and postnatal growth constitutes a risk factor for cardiovascular and kidney diseases as it induces alterations in blood pressure and renal function regulation in adult life.

Moderate zinc deficiency influences arterial blood pressure and vascular nitric oxide pathway in growing rats.

There is an increasing interest in the involvement of trace elements such as zinc in the pathogenesis of cardiovascular diseases. This study was designed to examine whether moderate zinc deficiency during growth influences blood pressure (BP) and vascular nitric oxide (NO) pathway. Three-week-old weaned male Wistar rats were randomly divided into two dietary groups and fed either a moderately zinc-deficient diet (zinc content 9 mg/kg; n = 12) or a control diet (zinc content 30 mg/kg; n = 12) for 60 d. The following were measured: systolic BP, nitrates and nitrites urinary excretion, urinary chemiluminescence intensity, NADPH-diaphorase activity in the thoracic aorta and intestinal arterioles, and NO synthase (NOS) catalytic activity using L-[U14C]-arginine as substrate in the thoracic aorta. Zinc deficiency during growth induced an increase in BP from day 30 of the experimental period, leading to hypertension on day 60. Animals that were fed the zinc-deficient diet had lower urinary excretion levels of nitrates and nitrites and higher intensity of spontaneous luminescence on day 60. At the end of the experiment, zinc-deficient rats showed decreased NADPH diaphorase activity in endothelium and smooth muscle of the thoracic aorta and intestinal arterioles and decreased activity of NOS in thoracic aortic tissue. An imbalance in zinc bioavailability during postnatal and growing periods may be may be a risk factor in development of cardiovascular alterations in adult life. The mechanisms involved may include an impaired vascular NO system as a result of decreased NOS activity and higher systemic oxidative stress.