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.
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
Understanding How Sepsis Causes Kidney Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$471,770.00
Summary
Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the las ....Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the last 50 years. The traditional view is that sepsis-induced renal failure results from reduced perfusion of the kidney secondary to the low blood pressure. In a model of sepsis in sheep with renal failure, we demonstrated, however, that renal blood vessels dilated and blood flow increased. Furthermore, renal function improved following treatment with vasoconstrictor drugs that raised blood pressure and renal blood flow. These findings indicate that renal ischaemia is not the cause of the renal dysfunction in sepsis. We hypothesise that sepsis causes renal vasodilatation, which reduces glomerular filtration rate and renal function, and induces a delayed development of apopotosis. We will study in sepsis 1) the effects of a treatment to increase glomerular filtration rate 2) the development of apoptosis and the effect of an anti-apoptotic drug, and 3) whether there is bioenergetic failure in the kidney in sepsis and the effects of treatments on this. Finally, in septic patients we will measure renal blood flow and determine the effects of our novel treatment on this and renal function. These studies will significantly increase our understanding of the factors causing acute renal failure in sepsis. They are likely to lead to the development of new therapies to improve renal function in sepsis and their effectiveness will be examined in septic animals and patients.Read moreRead less
RENAL VASCULAR HYPERTROPHY AND REMODELLING IN SHR: SYMPATHETIC NERVOUS SYSTEM AND IMPLICATIONS FOR HYPERTENSION
Funder
National Health and Medical Research Council
Funding Amount
$191,561.00
Summary
High blood pressure (hypertension) remains a major health problem for Australians. One in six Australians suffer from hypertension, with consequent increased risk of stroke and heart attack. Anti-hypertensive treatments are available, but must usually be taken for the rest of the patient's life and the cost to the taxpayer of anti-hypertensive drugs is greater than for any other health problem. Prevention of high blood pressure depends on identifying the initial cause - but we still do not know ....High blood pressure (hypertension) remains a major health problem for Australians. One in six Australians suffer from hypertension, with consequent increased risk of stroke and heart attack. Anti-hypertensive treatments are available, but must usually be taken for the rest of the patient's life and the cost to the taxpayer of anti-hypertensive drugs is greater than for any other health problem. Prevention of high blood pressure depends on identifying the initial cause - but we still do not know the cause in over 90% of hypertensive people. This project will study whether overactivity of the nerves to the blood vessels of the kidney might be the cause. There is evidence for this in humans, and in a strain of rats which develops high blood pressure (the spontaneously hypertensive rat). Our experiments will study these rats to see whether nerves affect the structure and function of the blood vessels of the kidney in ways that lead to increased blood pressure.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