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
New Insights Into The Role Of Renal Endothelial Dysfunction In The Pathogenesis Of Glomerular Injury And Renal Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$577,722.00
Summary
This project will ascertain whether abnormal function of endothelial cells contribute to diabetic and non-diabetic kidney diseases, the leading cause of end-stage kidney disease. The outcome of this study will allow us to reevaluate the role of endothelial cells in kidney scarring, lead us to question our current approaches to the treatment and management of chronic kidney disease and eventually may be helpful for the design of novel therapies to treat chronic kidney diseases.
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
Progressive Renal And Vascular Disease: Pivotal Role Of The AT2 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$283,875.00
Summary
Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the ....Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the beneficial effects particularly on the kidney of drugs which block this pathway. It has been demonstrated that angiotensin II acts via 2 different receptors, the AT1 and AT2 subtypes. Initially the AT1 receptor was viewed to mediate most of the biological effects of angiotensin II. However, as demonstrated by our own and other groups, the AT2 receptor may play a role in mediating various effects of angiotensin II particularly in disease states. We have identified expression of this receptor in the adult kidney and in the vessel wall which may be upregulated in various disease states. The status of the AT2 receptor is not well characterised in diabetes and many other kidney diseases and this proposal will address this issue in a comprehensive manner by evaluating various sites of injury in diabetes including the kidney and vascular tree. This proporsal includes different approach to moduate this receptor involving drug blockers and animal model where this receptoris either deleted or overexpressed. These studies potentially have major implications for the management of diabetic and renal complications. It remains to be determined if the AT2 receptor confers beneficial or deleterious effects in diabetic nephropathy or other renal diseases, if these effects vary among the various organs to be studied and whether AT2 receptor antagonists may themselves be of therapeutic value in individuals at high risk of kidney and vascular disease such as people with diabetes.Read moreRead less
Neural Versus Humoral Activation Of The Sympathetic Nervous System In Renal Disease
Funder
National Health and Medical Research Council
Funding Amount
$293,567.00
Summary
In the healthy body, the kidney and the sympathetic nervous system work together to keep our blood pressure in the normal range, both in the short and long term. When people have kidney disease, this system fails and people can develop high blood pressure. High blood pressure can lead to heart attack and stroke, and so is a serious complication for people who already have kidney disease. It has previously been believed that major factors in this process are fluid retention and a circulating horm ....In the healthy body, the kidney and the sympathetic nervous system work together to keep our blood pressure in the normal range, both in the short and long term. When people have kidney disease, this system fails and people can develop high blood pressure. High blood pressure can lead to heart attack and stroke, and so is a serious complication for people who already have kidney disease. It has previously been believed that major factors in this process are fluid retention and a circulating hormone called angiotensin II, but we believe that the sympathetic nervous system is also very important. Further, we believe that sensory nerves in the kidney tell the brain something is wrong in the kidney, making the sympathetic nervous system increase blood pressure inappropriately. We will examine the relative role of the sensory nerves and the hormone angiotensin II in driving the sympathetic nervous system to increase blood pressure, using three different rat models of kidney disease. One of these models is a new rat model of polycystic kidney disease, which is the fourth most important cause of renal disease in Australia. We want to determine what parts of the brain are important in the pathway, and will also test treatments that block the two different pathways (nerves vs. hormones) to see what is the most effective way of controlling not only blood pressure but also slowing down the progression of kidney and heart disease. This work is important as it will not only help us understand how the brain and kidney communicate with each other, but will also have the potential to improve quality of treatment for people with kidney diseaseRead moreRead less
Costimulation In Progressive Non-immune Tubulointerstitial Renal Disease.
Funder
National Health and Medical Research Council
Funding Amount
$434,875.00
Summary
Current treatments for chronic kidney disease are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year about 1700 Australians commence dialysis for this reason and many more die of kidney failure or its complications. This project will examine the role of costimulatory molecules in causing chronic kidney disease (CRD) to progress and their potential as targets for specific ....Current treatments for chronic kidney disease are non-specific and frequently ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year about 1700 Australians commence dialysis for this reason and many more die of kidney failure or its complications. This project will examine the role of costimulatory molecules in causing chronic kidney disease (CRD) to progress and their potential as targets for specific therapy to slow the progression of CRD. In chronic kidney diseases of all types, the kidney becomes infiltrated with inflammatory cells. The amount of inflammation has an important bearing on the severity of kidney failure and the rate at which kidney disease progresses. There are a range of different cells that invade the inflamed kidney, some may worsen disease while some may protect against it. Current treatments are non-selective and may, by suppressing inflammation, prevent both repair and protection. Costimulatory molecules have been shown to be important in the regulation of inflammatory cell activation in transplantation and some autoimmune diseases. We, and others, have evidence to suggest that costimulatory molecules may be pivotal to the development and progression of kidney inflammation in CRD as well. This project will use two robust animal models of human CRD to define the role of costimulatory molecules in progression of kidney disease. If, as our preliminary evidence suggests, costimulatory molecules are shown to alter disease progression, then they will provide excellent targets for new treatments. Eventually, treatment directed against costimulatory molecules may be used as more effective and safer therapy for human kidney disease.Read moreRead less
EFFECTOR AND REGULATORY INTERSTITIAL INFLAMMATORY CELLS IN CHRONIC PROTEINURIC RENAL DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$289,150.00
Summary
Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year almost 1600 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. This project will lead to a greater understanding of why kidney failure progresses, and will define more effective treatments for preventing progression. In progressive chronic kidney ....Current treatments for chronic kidney disease are ineffective. As a consequence, kidney failure progresses to the stage where patients require dialysis or transplantation to remain alive. Every year almost 1600 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. This project will lead to a greater understanding of why kidney failure progresses, and will define more effective treatments for preventing progression. In progressive chronic kidney diseases of all types, the supporting tissue within the kidney (the interstitium) becomes infiltrated with inflammatory cells. The amount of interstitial inflammation has an important bearing on the severity of kidney failure, and the rate at which kidney disease progresses to endstage. The reasons that these inflammatory cells infiltrate the interstitium, and their exact role in the progression of kidney disease are only partially understood. For example, some of these inflammatory cells appear to cause kidney scarring, whereas others appear to be protective. Moreover, even though they are obvious targets for treatment aimed at slowing the progression of kidney disease, current treatments are largely ineffective as they do not differentiate between the different types of inflammatory cells, and whether these cells are causing or preventing damage. Our laboratory has recently developed a robust model of chronic kidney disease, which will be used to examine the effect of individual types of interstitial inflammatory cells on the progression of kidney disease. So far we have shown that depletion of one type of inflammatory cell (CD4 lymphocytes) worsened the disease process, whereas depletion of two other cell types (CD8 lymphocytes or macrophages) was protective. This raises the real and exciting possibility that treatment directed against specific inflammatory cells may be effective in the treatment of progressive kidney disease in humans.Read moreRead less
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 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