Current Drug Targets

ISSN: 1389-4501

Current Drug Targets
Volume 8, Number 8, August 2007

Contents

Nutrition
Guest Editor: Michael E. Symonds


Impact of Periconceptional Undernutrition on the Development of the Hypothalamo-Pituitary-Adrenal Axis: Does the Timing of Parturition Start at Conception Pp. 880-887
S.M. MacLaughlin and I.C. McMillen
[Abstract]


Maternal Nutrient Restriction is not Equivalent to Maternal Biological Stress Pp. 888-893
H. Budge, T. Stephenson and M.E. Symonds
[Abstract]


Fetal Mechanisms That Lead to Later Hypertension Pp. 894-905
D.S. Gardner, R.C. Bell and M.E. Symonds
[Abstract]


Maternal Nutrition and Predisposition to Later Kidney Disease Pp. 906-913
L.L. Woods
[Abstract]


Influences of Maternal Nutritional Status on Vascular Function in the Offspring Pp. 914-922
L. Poston
[Abstract]


Is Later Obesity Programmed In Utero Pp. 923-934
M.H. Vickers, S.O. Krechowec and B.H. Breier
[Abstract]


Fetal Determinants of Type 2 Diabetes Pp. 935-941
B. Reusens, S.E. Ozanne and C. Remacle
[Abstract]


General Articles


Statins Exert Multiple Beneficial Effects on Patients Undergoing Percutaneous Revascularization Procedures Pp. 942-651
K.I. Paraskevas, V.G. Athyros, D.D. Briana, A.I. Kakafika, A. Karagiannis and D.P. Mikhailidis
[Abstract]


Molecular Mechanisms of Diabetic Nephropathy and Its Therapeutic Intervention Pp. 952-959
S.-i. Yamagishi, K. Fukami, S. Ueda and S. Okuda
[Abstract]




Abstracts

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Impact of Periconceptional Undernutrition on the Development of the Hypothalamo-Pituitary-Adrenal Axis: Does the Timing of Parturition Start at Conception
S.M. MacLaughlin and I.C. McMillen

There are a number of critical windows during prenatal and postnatal life and a range of potential agents including exposure to maternal and fetal stressors, nutrition, and antenatal administration of synthetic glucocorticoids and postnatal maternal care and behaviour that are important in programming the subsequent reactivity of the HPA axis. Recently, it has become clear that the periconceptional period is also an important critical period during which changes in the level of maternal nutrition result in altered development of the fetal HPA axis. These findings have potential implications for the ability of the fetus to respond to acute and chronic stressors, for the timing of parturition and have potential implications for adult cardiovascular and metabolic health outcomes. In this review we focus on the different models which have been used to investigate the impact of maternal undernutrition during the periconceptional period on the prepartum activation of the fetal HPA axis. We propose that the term “periconceptional” should be used to refer to the developmental stages which include some or all of the following early events: oocyte maturation, follicular development, conception, and embryo/blastocyst growth up until implantation. When maternal undernutrition extends beyond implantation, up until early placentation, then it is appropriate to describe maternal undernutrition as occurring during ‘early gestation’. Further work is required to define the relative contributions of nutritional factors operating in the periconceptional and early gestational periods on the programming of the subsequent development of the HPA axis and is of importance for fetal, postnatal and subsequent adult cardiovascular and metabolic health.


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Maternal Nutrient Restriction is not Equivalent to Maternal Biological Stress
H. Budge, T. Stephenson and M.E. Symonds

An increase in fetal glucocorticoid exposure has long been considered to be a primary mechanism by which maternal nutritional manipulation may result in long term adaptations in the fetus such that it is at increased risk of a range of adult diseases including hypertension, diabetes and obesity. Animal studies in which high doses of synthetic glucocorticoids have been administered to the mother shown some long term programming effects, but these are nearly always accompanied by a reduction in maternal food intake. In this review, we will, therefore, consider the extent to which maternal food restriction and elevated maternal glucocorticoid concentrations can result in the same or different adaptations within the fetus such that they exhibit developmental changes in blood pressure control and/or metabolic homeostasis. One factor that appears to be critical in determining the mother’s response is the stage of gestation at which her nutrient intake is manipulated. This may be explained in part by the placenta’s ability to inactivate glucocorticoids. Irrespective of the mechanisms involved, it is clear that long term tissue specific adaptations within a range of organs, including adipose tissue and the kidney, can be greatly altered following changes in maternal glucocorticoid secretion.

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Fetal Mechanisms That Lead to Later Hypertension
D.S. Gardner, R.C. Bell and M.E. Symonds

Extensive epidemiological and experimental evidence suggests the nutritional environment in which a developing conceptus is exposed is a major factor determining later cardiovascular disease. In this review a consideration of the extent to which altered maternal/fetal nutritional environments may predispose toward later anomalies in blood pressure control and hypertension will be undertaken. In particular, a focus will be on potentially novel mechanistic pathways through which early-mid gestational undernutrition may impact upon fetal/adult adipocyte, renal and brain function, that act to increase the risk of later hypertension developing. Within the review we shall also present an opinion on the differing animal models that are currently employed to address developmental programming and introduce a conceptual frame-work that synthesises current available evidence.

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Maternal Nutrition and Predisposition to Later Kidney Disease
L.L. Woods

Although it is well-accepted that size at birth is inversely related to adult blood pressure and cardiovascular risk in humans, the majority of information available with regard to maternal nutrition, prenatal growth, and subsequent renal disease comes from animal models. Restriction of food or protein during specific windows of pregnancy leads to hypertension in adult offspring. Depending on the degree of maternal restriction, nephron number and renal function in the offspring may be reduced, and proteinuria and histological signs of renal disease are present. All of these abnormalities appear to worsen with age. Female gender is relatively protective against these prenatal insults, but with more severe maternal dietary restriction female offspring are also affected. In addition to macronutrients, roles for several micronutrients have been identified in fetal programming for hypertension and renal disease. Ongoing investigations into the roles of sex hormones, the renin-angiotensin system, and vitamin A in these developmental processes may lead to strategies for prevention of dietary programming for hypertension and renal disease in humans.


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Influences of Maternal Nutritional Status on Vascular Function in the Offspring
L. Poston

Fetal growth restriction leading to low birthweight is associated with increased risk of ischaemic heart disease and hypertension in later life. Increasingly, it is recognised that cardiovascular risk may also be initiated in early life when the fetus and neonate are exposed to maternal nutritional excess. This review summarises the studies in man and animals that have investigated the potential role of vascular disorders in the aetiology of atherosclerosis and hypertension arising from early life nutritional deprivation or excess. Malfunction of the arterial endothelial cell layer in the offspring has been frequently described in association with both maternal under and overnutritional states and may play a permissive role in the origin of these disorders. Also prevalent is evidence for increased stiffness of the large arteries which may contribute to systolic hypertension. Further investigation is required into the intriguing suggestion that early life nutritional imbalance may adversely influence vascular angiogenesis leading to rarefaction and increased peripheral vascular resistance.


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Is Later Obesity Programmed In Utero
M.H. Vickers, S.O. Krechowec and B.H. Breier

The global prevalence of obesity has increased markedly over the last two decades with over 50% of all adults in the UK and USA classified as overweight or obese. Furthermore, the prevalence of obesity in children has risen by over 40% in the last 16 years. Obesity results from the interaction of many factors, including genetic, metabolic, behavioral, and environmental influences. However, the rate at which obesity is increasing suggests that environmental and behavioral influences, rather than genetic changes, have fueled the epidemic. In this context, it is of particular relevance that epidemiological and experimental studies have highlighted a relationship between the periconceptual, fetal and early infant phases of life and the subsequent development of adult adiposity. This relationship; the “developmental origins of health and disease” (DOHaD) model, speculates that the fetus adapts to adverse environmental cues in utero with permanent readjustments in homeostatic systems to aid survival. However, these adaptations, known as predictive adaptive responses, may ultimately be disadvantageous in postnatal life and may lead to an increased risk of chronic non-communicable disease in adulthood. This review summarises recent work in animal models and observations in the clinical and epidemiological settings on the in-utero origins of obesity and related metabolic disorders.


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Fetal Determinants of Type 2 Diabetes
B. Reusens, S.E. Ozanne and C. Remacle

Type 2 diabetes, which has dramatically increased during the last decade normally results from a combination of pancreatic beta cell dysfunction and insulin resistance. One of the most recent risk factors identified for type 2 diabetes is a sub-optimal fetal and neonatal environment. Numerous human epidemiological studies worldwide have highlighted that a disturbed nutritional environment of the fetus, either poor or too abundant will compromise the health of the offspring by increasing the susceptibility to insulin resistance, to glucose intolerance and to diabetes in later life. In addition to adverse intrauterine events, the detrimental role of catch-up growth and of the mismatch between the prenatal and the postnatal metabolic environment in such pathology is now clear. To understand the mechanisms that are responsible for such programming and to be able to design prevention strategies, a number of animal models have been created. This manuscript reviews the data from several rodent models in which maternal or neonatal diet has been altered. These include models of maternal under-nutrition and over-nutrition as well as gestational diabetes. In general, abnormal beta cell mass and beta cell dysfunction are present at birth and insulin resistance, glucose intolerance and diabetes appear in adult offspring. Obesity, pregnancy and ageing exaggerate the phenotype and there is some evidence to suggest that the pheno-type can be transmitted to a second generation independently of any further environmental modification. Possible underlying mechanisms are discussed and evidence for potential early intervention strategies are reported


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Statins Exert Multiple Beneficial Effects on Patients Undergoing Percutaneous Revascularization Procedures
K.I. Paraskevas, V.G. Athyros, D.D. Briana, A.I. Kakafika, A. Karagiannis and D.P. Mikhailidis

Background and aims: Statins are an essential component of the therapeutic approach of patients with atherosclerotic disease. Statin use is also associated with improved peri-operative and long-term outcomes in these patients. We aimed to define the role of statin treatment in patients undergoing percutaneous revascularization procedures.

Literature search method: We searched Medline for studies assessing the effect of statin treatment on percutaneous interventions.

Literature search results: Early statin treatment is associated with improved outcomes in patients undergoing percutaneous coronary intervention procedures. Current evidence implies that statin treatment may also play a beneficial role in the management of patients undergoing percutaneous renal artery revascularization and endovascular abdominal aortic aneurysm repair, carotid angioplasty/stenting and endovascular peripheral arterial interventions.

Conclusions: Preliminary data suggest that statins exert multiple beneficial actions in patients undergoing percutaneous interventions. Future randomized trials are expected to further evaluate the beneficial effects of statins in these procedures.


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Molecular Mechanisms of Diabetic Nephropathy and Its Therapeutic Intervention
S.-i. Yamagishi, K. Fukami, S. Ueda and S. Okuda

Diabetic nephropathy is a leading cause of end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and hemodynamic factors, which activate common pathways that lead to renal damage. Recent large landmark clinical studies have shown that intensive glucose control reduces the risk of the development and progression of diabetic nephropathy, and the blockade renin-angiotensin system (RAS) is also an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. However, diabetic nephropathy remains the leading cause of end-stage renal failure in developed countries. Therefore, to develop novel therapeutic strategies that specifically target diabetic nephropathy may be helpful for most patients with diabetes. High glucose, via various mechanisms such as increased production of oxidative stress and advanced glycation end products (AGEs), and activation of the RAS and protein kinase C (PKC), elicits vascular inflammation and alters gene expression of growth factors and cytokines, thereby it might be involved in the development and progression of diabetic nephropathy. This article summarizes the molecular mechanisms of diabetic nephropathy and the potential therapeutic interventions that may prevent this devastating disorder even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.