The kidneys of infants born preterm continue to develop after birth. However, preterm infants are exposed to high oxygen levels which may impact on ongoing development. In a rodent model of oxygen exposure, the blood vessels of the kidney and the numbers of stem cells will be assessed; additionally, further stem cells will be administered in order to try and prevent any impairment. It is expected that the findings of this study will help to explain the effects of preterm birth on the kidney.
The Effects Of Pre-term Birth On The Baboon And Human Neonatal Kidney
Funder
National Health and Medical Research Council
Funding Amount
$349,248.00
Summary
LAY DESCRIPTION: Over the past two decades the incidence and survival after pre-term birth has increased substantially. Despite significant improvements in the treatment of these pre-term babies there remains a high incidence of kidney failure. The functional unit of the kidney is the nephron and they are formed in the kidney late in pregnancy at a time when many preterm babies are already delivered. Hence, it is important to determine what is the effect of preterm birth on the formation of neph ....LAY DESCRIPTION: Over the past two decades the incidence and survival after pre-term birth has increased substantially. Despite significant improvements in the treatment of these pre-term babies there remains a high incidence of kidney failure. The functional unit of the kidney is the nephron and they are formed in the kidney late in pregnancy at a time when many preterm babies are already delivered. Hence, it is important to determine what is the effect of preterm birth on the formation of nephrons. We have shown that the baboon is an excellent model of kidney development in humans. Like humans, we can prematurely deliver baboons and maintain them in a neonatal intensive care unit after birth. In this model, we have evidence to suggest that the formation of the the nephrons within the kidneys of the pre-term infants is impaired and we predict that this leads to impaired kidney function after birth and to susceptibility for renal disease in adulthood. In this study, we will examine kidney function in preterm baboon and human babies and also undertake studies in autopsied kidneys from baboon and human pre-term infants. We will determine whether the number and the cellular structure of the nephrons is affected by preterm delivery and if so, whether kidney function is affected. By comprehensively examining the medical records of the mother and babies, we also aim to identify factors in the care of the mother prior to birth, or of the baby after birth which may link to impaired nephron formation and kidney dysfunction in the baby. We will also determine whether administration of retinoic acid to the baboon preterm baby soon after birth can stimulate the formation of nephrons. The findings of this study will provide important new insights into the mechanisms of kidne failure in preterm babies and will identify potential strategies to prevent nephron loss and enhance nephron formation in preterm infants, which will in turn have long-term implications to kidney health.Read moreRead less
Exploring The Physiological, Morphological And Molecular Bases Of Renal Developmental Programming.
Funder
National Health and Medical Research Council
Funding Amount
$422,264.00
Summary
Suboptimal fetal and neonatal development increases our risk of developing a range of diseases in adulthood. The concept that deleterious events during development can influence adult health is termed 'developmental programming'. Obtaining A Healthy Start to Life is a priority research goal of the Australian Government. The kidneys are particularly susceptible to developmental programming. This is in part because the functional units (nephrons) of the kidneys are all formed before birth in human ....Suboptimal fetal and neonatal development increases our risk of developing a range of diseases in adulthood. The concept that deleterious events during development can influence adult health is termed 'developmental programming'. Obtaining A Healthy Start to Life is a priority research goal of the Australian Government. The kidneys are particularly susceptible to developmental programming. This is in part because the functional units (nephrons) of the kidneys are all formed before birth in humans. Thus, if fetal development is suboptimal, babies are at risk of being born with a permanent nephron deficit, with functional and disease consequences. We have shown in male rats that the offspring of a maternal low protein diet have fewer nephrons and lower blood pressure than rats fed a normal diet. These rats display a striking sensitivity in adulthood to the feeding of a high salt diet. We will define the physiological and morphological bases of this sensitivity, and repeat these studies in females, as increasing evidence shows significant sex differences in developmental programming. Defining the molecular mechanisms of developmental programming is the greatest challenge for researchers in the field. We have recently completed the most comprehensive analysis to date of gene expression in the developing mouse kidney, and have shown for the first time that the mouse programmes kidney development. We will use the new techniques of genomics and bioinformatics to study the molecular mechanisms of kidney programming. This mechanistic data will provide an excellent hypothesis engine for future studies on the specific roles of these molecular pathways in developmental programming in all mammalian species.Read moreRead less
Prenatal Placental And Postnatal Mammary Programming Of Cardiovascular And Renal Diseases
Funder
National Health and Medical Research Council
Funding Amount
$503,776.00
Summary
Being born small and the associated catch-up growth, independently predict adult hypertension. Reduced placental blood flow is a major cause of fetal growth restriction and is implicated in programming adult disease. We are the first to demonstrate that placental compromise in rats also adversely affects breast development, milk quality and supply, which further impair growth during lactation. This is followed by accelerated growth after weaning, programming more adverse outcomes. Using a rat mo ....Being born small and the associated catch-up growth, independently predict adult hypertension. Reduced placental blood flow is a major cause of fetal growth restriction and is implicated in programming adult disease. We are the first to demonstrate that placental compromise in rats also adversely affects breast development, milk quality and supply, which further impair growth during lactation. This is followed by accelerated growth after weaning, programming more adverse outcomes. Using a rat model, we will determine for the first time if restricted nutrition before birth via the placenta or after birth via lactation increases the risk of developing high blood pressue and kidney and blood vessel dysfunction. Manipulations of nutrition after birth will be achieved by cross-fostering studies. We will establish whether a reduction in the number of functioning units (nephrons) in the kidney, alterations in key genes involved in kidney development and changes in blood vessel reactivity are associated with developing hypertension. We will manipulate the renin-angiotensin system (RAS), which is important in determining kidney function, to define its role in hypertension in this model. We propose that a common lifestyle insult, such as modest elevation in dietary salt, will evoke exaggerated responses in adult offspring who were born small. These studies will identify the mechanisms by which the kidney, vasculature and RAS contribute to the programming of hypertension and the relative roles of the prenatal and postnatal environments. Defining the underlying mechanisms responsible will provide insight into early life interventions that may lessen these adverse consequences for longer-term health. Identification of critical periods after birth, rather than before, would offer a greater likelihood that practical public health interventions can be developed to improve adult health in this emerging field.Read moreRead less
Vitamin D Deprivation In Early Life: Programming Of Vascular Function In Adulthood
Funder
National Health and Medical Research Council
Funding Amount
$440,250.00
Summary
It is becoming increasing evident that appropriate nutrition in fetal-early life is important in programming the cardiovascular system of the offspring, influencing its function throughout life. Maternal deficiency in vitamin D is a recently-identified concern world-wide, including in Australian women. We have recently found that vitamin D deficiency in pregnant rats results in marked hypertension in the offspring, when only 7 weeks of age. This is associated with impaired endothelium-dependent ....It is becoming increasing evident that appropriate nutrition in fetal-early life is important in programming the cardiovascular system of the offspring, influencing its function throughout life. Maternal deficiency in vitamin D is a recently-identified concern world-wide, including in Australian women. We have recently found that vitamin D deficiency in pregnant rats results in marked hypertension in the offspring, when only 7 weeks of age. This is associated with impaired endothelium-dependent vasodilator function, increased smooth muscle tone and increased constriction to nerve stimulation. A combination of intracellular electrophysiological techniques and tension recordings will be used to investigate detailed mechanisms in arteries isolated from key vascular beds. In vivo studies will probe the role of vitamin D deficiency in the control of regional blood flow control, and its influence on the underlying regulatory mechanisms responsible for the cardiovascular dysfunction that we have observed. We will test whether the cardiovascular dysfunction in the offspring following vitamin D deficiency is reversible upon repletion, or is programmed and thus not reversible with repletion. Our early results suggest that the deleterious effects are not reversible. From this study we aim to be in a position of greater confidence from which to inform women as to the importance for their baby of ensuring adequate vitamin D repletion during pregnancy, to minimise risk of later cardiovascular disease.Read moreRead less