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
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
A Randomised Trial Of The Effects Of Cholesterol Lowering Therapy Among Patients With Chronic Renal Impairment
Funder
National Health and Medical Research Council
Funding Amount
$333,250.00
Summary
People with kidney disease are well known to be at high risk of developing major health problems earlier in life than people without kidney problems. In particular, people with kidney disease are more likely to suffer from heart attacks and strokes. For a number of other high-risk patient groups (such as people with heart disease), studies have clearly shown that cholesterol-lowering treatment can significantly reduce the risks of serious complications. However, until now, patients with kidney d ....People with kidney disease are well known to be at high risk of developing major health problems earlier in life than people without kidney problems. In particular, people with kidney disease are more likely to suffer from heart attacks and strokes. For a number of other high-risk patient groups (such as people with heart disease), studies have clearly shown that cholesterol-lowering treatment can significantly reduce the risks of serious complications. However, until now, patients with kidney disease have generally been excluded from such studies because of concerns about drug side effects. New, better-tolerated cholesterol lowering drugs now offer an opportunity to see if this highly effective treatment is also protective among people with kidney disease. The HARP (Heart And Renal Protection) trial is a large new study that will be done as a collaboration between Australian researchers and researchers from the University of Oxford in the UK. The aim of the study is to see if low doses of two cholesterol-lowering drugs can reduce the risks of stroke and heart attack. The study will include about 9,000 people with chronic kidney disease followed for an average of 4 years. It is hoped that by using low doses of two treatments, rather than a high dose of one, it will be possible to get substantial benefits without side effects. There are presently many tens of thousands of individual in Australia with chronic kidney disease and many millions of such individuals worldwide. The results of the HARP study will therefore influence the care of a very large number of people. If the results were positive, implementation of this new treatment would be expected to prevent many tens of thousands of premature strokes and heart attacks around the world each year.Read moreRead less
Centre Of Clinical Research Excellence In Renal Medicine
Funder
National Health and Medical Research Council
Funding Amount
$2,000,000.00
Summary
This Centre aims to answer important research questions such as: Does screening for early renal disease prevent kidney failure? Does renal disease in Aboriginal people begin in early childhood? What causes transplanted kidneys to fail? With the worldwide editorial base of the Cochrane Renal Group, the editorial base on the National Guidelines on Renal Disease and close links with the Master of Medicine (Clinical Epidemiology) program at the University of Sydney, this Centre will also provide pro ....This Centre aims to answer important research questions such as: Does screening for early renal disease prevent kidney failure? Does renal disease in Aboriginal people begin in early childhood? What causes transplanted kidneys to fail? With the worldwide editorial base of the Cochrane Renal Group, the editorial base on the National Guidelines on Renal Disease and close links with the Master of Medicine (Clinical Epidemiology) program at the University of Sydney, this Centre will also provide proven mechanisms for clinical research training and translation of research findings into clinical practice.Read moreRead less
The Role Of The Cytoplasmic Domain Of Tissue Factor In Maintenance Of The Glomerular Filtration Barrier.
Funder
National Health and Medical Research Council
Funding Amount
$487,066.00
Summary
This research aims to understand mechanisms of normal kidney function and the development of chronic kidney damage associated with diseases such as nephritis and diabetes. These diseases represent a significant burden of illness in Australia.
Treatment Of Chronic Proteinuric Renal Disease With DNA Vaccines Against TCR Subsets Of Effector T Cells And Chemokines
Funder
National Health and Medical Research Council
Funding Amount
$282,750.00
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 develop and test a novel therapeutic strategy of DNA vaccination targeted specifically at groups of white cells, and specific regulatory mo ....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 develop and test a novel therapeutic strategy of DNA vaccination targeted specifically at groups of white cells, and specific regulatory molecules in order to prevent chronic kidney disease (CPRD). In chronic kidney diseases of all types, the kidney filters and surrounding tissue becomes infiltrated with inflammatory cells. The amount of inflammation in the filters and the tissues 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 worsen the disease while some may protect against it. Current treatments are non-selective and may, by suppressing inflammation, prevent both repair and protection. We have established a central role for two groups of white cells called macrophages and T lymphocytes in two animal models of kidney disease. In one of these models, we used DNA vaccination, which represents a novel means of switching off these disease-causing T cells. The results showed that DNA vaccination against T cell subsets was protective in our model. This raises the real and exiting possibility that DNA vaccination directed at specific disease-causing cells, and their products are much more likely to be specific and effective therapy for chronic kidney diseases. Eventually, such DNA vaccination may be used as a more effective and safer therapy for human kidney disease.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.
To Improve The Accuracy And Precision Of Estimated GRF (eGFR) Measurements In Indigenous Australians
Funder
National Health and Medical Research Council
Funding Amount
$959,349.00
Summary
There is an overwhelming burden of chronic disease in Indigenous Australians. In order to attempt to improve kidney disease in this high-risk population, it is vital that we are able to accurately measure kidney function. This study will provide evidence to accurately assess kidney function in Indigenous Australians. This will then enable development of appropriate clinical guidelines and more effective monitoring of future interventions to slow progression of kidney disease.