The Effects Of Maternal Health On Fetal Kidney Development And Its Function
Funder
National Health and Medical Research Council
Funding Amount
$297,338.00
Summary
There is an epidemic of renal disease among Australian aborigines. While much of this could have been prevented by effective control of Group A streptococcal skin infections, there is also evidence that the high susceptibility to end-stage renal disease is related to poor intrauterine development of the kidney as low- birth weight is a predisposing factor. Mothers, whose renal function is impaired, tend to have babies which are low birth weight. There is no knowledge about the effects of materna ....There is an epidemic of renal disease among Australian aborigines. While much of this could have been prevented by effective control of Group A streptococcal skin infections, there is also evidence that the high susceptibility to end-stage renal disease is related to poor intrauterine development of the kidney as low- birth weight is a predisposing factor. Mothers, whose renal function is impaired, tend to have babies which are low birth weight. There is no knowledge about the effects of maternal renal dysfunction on development of the fetal kidney. We have recently developed an animal model in which we can study the effects of maternal renal dysfunction on the development of the kidney of her offspring. Human beings form 60% of the functional units (nephrons) in the kidney in the last trimester. Sheep, like human beings (and unlike rats), completely form all the nephrons that they will ever have, during intrauterine life. While the fetal kidneys play an essential role in the formation of amniotic fluid, regulation of fetal fluid and electrolyte homeostasis depends on maternal renal function via transplacental transfer. If maternal renal function is reduced, it is likely that the fetal kidneys will be exposed to a greater volume and solute load through transplacental equilibration. This may have a profund effect on renal development especially if coupled with an inadequate maternal diet and a high maternal salt intake. Under these conditions we predict that development of the fetal kidney will be impaired and renal capacity after birth, reduced. This means that the kidney will 'age' more rapidly. Thus the affected individual would be predisposed to renal disease in adult life. In our animal model we will study the effects and interactions of maternal renal insufficiency, poor fetal nutrition and a high maternal salt intake on fetal kidney development and function.Read moreRead less
Effects Of Prenatal Alcohol Exposure On The Developing Kidney
Funder
National Health and Medical Research Council
Funding Amount
$602,636.00
Summary
Almost 50% of Australian women consume alcohol when they are pregnant. Although it is generally thought that low levels of consumption (one-two standard drinks per day) are not harmful to the fetus, no study has examined the effect of this level of alcohol consumption on the development of the kidney and the long term renal and cardiovascular function of the offspring. We shall identify if low levels of exposure to ethanol can alter kidney development and impact on long-term health.
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.
NEPHROTOXICITY OF ANGIOTENSIN INHIBITION DURING RENAL DEVELOPMENT
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
Renal dysplasia and renal cystic disease remain significant clinical problems in the paediatric population. Initial animal experiments have demonstrated that inhibiting the renal vasoactive peptide angiotensin during development results in a form of medullary cystic disease. The experiments in this project are aimed at understanding the specific roles and interactions that angiotensin plays in renal development, particularly in development of the distal nephron, the vasculature and the renal pel ....Renal dysplasia and renal cystic disease remain significant clinical problems in the paediatric population. Initial animal experiments have demonstrated that inhibiting the renal vasoactive peptide angiotensin during development results in a form of medullary cystic disease. The experiments in this project are aimed at understanding the specific roles and interactions that angiotensin plays in renal development, particularly in development of the distal nephron, the vasculature and the renal pelvis. Importantly the time course of growth and differentiation of these structures varies and the time course of inactivation of angiotensin may result in different malformations. Information from these studies will allow us to understand how clinical problems can arise when angiotensin is absent or other players modify its action. Such situations can arise in humans through sporadic genetic mutations that may well not manifest in widespread clinical abnormalities.Read moreRead less
The Role Of Crim1, A Novel TGFb Superfamily Modulator, In Early Vertebrate Patterning, Vascular And Renal Development.
Funder
National Health and Medical Research Council
Funding Amount
$501,300.00
Summary
The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be dele ....The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be deleterious, with their overexpression leading to conditions such as renal fibrosis and cataract. The activity of these growth factors is regulated by many other proteins, including protein antagonists which bind and inactivate them. It is therefore possible that by understanding these antagonists, we can find new ways of altering TGF beta superfamily activity. We have previously identified a novel protein, Crim1, which we have now shown can bind to TGF superfamily members and can reduce their secretion. We believe that Crim1 plays a role in the patterning of the central nervous system, the development of the blood vessels and the kidneys by regulating the TGFbeta superfamily. In this grant we will be investigating what the effect of disruption to Crim1 is on these organ systems and working out which members of the TGFbeta superfamily it is affecting to cause these effects. To do this, we will knock out the gene in zebrafish and characterise the defects found in a mouse line in which the gene has been disrupted. This may be important in developing new ways of activating or inactiviating these growth factors in a number of clinical conditions.Read moreRead less
Single Nephron GFR And Tubuloglomerular Feedback Before And After Birth.
Funder
National Health and Medical Research Council
Funding Amount
$402,428.00
Summary
In this project we want to study the forces responsible for the filtration of plasma by the kidney during development. This process is the first step in urine production. It is important to understand kidney function because abnormalities in kidney function can result in high blood pressure and chronic renal disease (requiring dialysis or transplant) in later life. It is reported that up to 40% of the population is salt sensitive i.e. their blood pressure increases when they are on a high salt d ....In this project we want to study the forces responsible for the filtration of plasma by the kidney during development. This process is the first step in urine production. It is important to understand kidney function because abnormalities in kidney function can result in high blood pressure and chronic renal disease (requiring dialysis or transplant) in later life. It is reported that up to 40% of the population is salt sensitive i.e. their blood pressure increases when they are on a high salt diet. The cause of this salt sensitivity is unknown but we believe that it could be due to abnormalities in kidney function during fetal life. Alterations in function occuring during development can have life long effects through a process called fetal programming.Read moreRead less
Stress-induced Disease Risk For Pregnant Mothers Born Small
Funder
National Health and Medical Research Council
Funding Amount
$613,124.00
Summary
This proposal addresses the likelihood that mothers born small and exposed to stress during pregnancy will develop adverse physiological adaptations to pregnancy, slowing placental and fetal growth, programming intergenerational disease and compromising maternal health later in life. The outcomes from our human and rat studies will enable development of diagnostic tests to identify pregnancies at greater risk and lead to therapies to reduce adverse intergenerational and long-term health effects.
We have shown that premature birth leads to abnormalities in kidney structure and function. This project will determine in human infants, whether premature birth when combined with poor growth in the womb leads to an increase in these kidney abnormalities. Using animal studies we will examine specific factors which may adversely impact on kidney growth before and after premature birth. The findings are very relevant to the long-term kidney health of indigenous Australians.