Role Of The Podocyte In Diabetic Nephropathy: Structural, Functional, Molecular And Interventional Studies
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Kidney disease is a major cause of disability and premature death in the Australian population. In disease the kidney's ability to filter out impurities and toxins in blood is impaired as a consequence of excessive cell growth and scar tissue formation. Studies from our group indicate that a highly specialised cell within the kidney's filtering apparatus becomes altered early in the course of diabetes. In the setting of diabetes, this cell, called the podocyte, stretches and begins forming scar ....Kidney disease is a major cause of disability and premature death in the Australian population. In disease the kidney's ability to filter out impurities and toxins in blood is impaired as a consequence of excessive cell growth and scar tissue formation. Studies from our group indicate that a highly specialised cell within the kidney's filtering apparatus becomes altered early in the course of diabetes. In the setting of diabetes, this cell, called the podocyte, stretches and begins forming scar tissue. In addition, it no longer maintains its barrier function and starts to leak protein. The proposed studies will explore the mechanisms that lead to these diabetes-induced changes in the podocyte. In addition, strategies for reversing these changes will also be explored in detail with the aim of providing new treatments for diabetic kidney disease.Read moreRead less
Molecular Mechanisms Of Macrophage-mediated Renal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$437,036.00
Summary
The complete loss of kidney function means that survival of the patient is dependent upon lifelong dialysis or a kidney transplant. Dialysis patients have a poor quality of life, and the provision of dialysis and transplantation treatments are very costly. Our current therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to understanding the way in which the kidney is damaged in disease in order to identify new and specific approaches to the tr ....The complete loss of kidney function means that survival of the patient is dependent upon lifelong dialysis or a kidney transplant. Dialysis patients have a poor quality of life, and the provision of dialysis and transplantation treatments are very costly. Our current therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to understanding the way in which the kidney is damaged in disease in order to identify new and specific approaches to the treatment of kidney disease. Our studies have shown that white blood cells, called macrophages, enter the kidney in large numbers during disease. Indeed, the greater the number of macrophages within the kidney, the more severe the kidney injury. We believe, on the basis of animal studies, that these macrophages cause kidney injury. However, we do not know the mechanisms by which this happens. To address this question, we have developed a rat model of kidney disease in which we can take macrophages, which we have cultured in the laboratory, and inject them into animals and they will enter the kidney and cause injury. This allows us to modify specific macrophage functions in culture and then determine whether this affects the ability of these macrophages to cause kidney injury in the animal. In this way, we will be able to understand the mechanisms by which macrophages cause kidney injury. We hope that these studies will can be a starting point for the development of new and specific approaches to the treatment of human kidney disease.Read moreRead less
Molecular Mechanisms Of Macrophage-mediated Renal Injury.
Funder
National Health and Medical Research Council
Funding Amount
$59,756.00
Summary
The complete loss of kidney function means that survival of the patient is dependent upon lifelong dialysis or a kidney transplant. Dialysis patients have a poor quality of life, and the provision of dialysis and transplantation treatments are very costly. Our current therapies reply upon steroids and cytotoxic drugs. These therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to develop new and specific approaches to the treatment of kidney di ....The complete loss of kidney function means that survival of the patient is dependent upon lifelong dialysis or a kidney transplant. Dialysis patients have a poor quality of life, and the provision of dialysis and transplantation treatments are very costly. Our current therapies reply upon steroids and cytotoxic drugs. These therapies have only limited efficacy and are associated with significant side-effects. Therefore, we need to develop new and specific approaches to the treatment of kidney disease. To do this, we need to begin by understanding the way in which the kidney is damaged in disease. Our studies have shown that white blood cells, called macrophages, enter the kidney in large numbers during disease. Indeed, the greater the number of macrophages within the kidney, the more severe the kidney injury. We believe, one the basis of animal studies, that these macrophages cause kidney injury. However, we do not know the mechanisms by which this happens. To address this question, we have developed a rat model of kidney disease in which we can take macrophages, which we have cultured in the laboratory, and inject them into animals and they will enter the kidney and cause injury. This allows us to modify specific macrophage functions in culture and then determine whether this affects the ability of these macrophages to cause kidney injury in the animal. In this way, we will be able to understand the mechanisms by which macrophages cause kidney injury. We hope that these studies will enable us to develop new and specific approaches to the treatment of 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
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
DNA Vaccination Using Chemokine And Costimulatory Pathways As A Treatment For Chronic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$450,390.00
Summary
Chronic kidney disease (CKD) is a great burden on Australia. Treatments are mostly ineffective. Our DNA vaccination against mediators of inflammation can protect against CKD. On the basis of ongoing studies we have identified 5 candidate molecules involved in recruitment and activation of inflammatory cells. We outline studies to generate DNA vaccines to these molecules, enhance their efficacy, and test them in models that represent the 3 most important causes of human CKD.
MODIFICATION OF TUBULE CELL CYTOKINES REGULATING INTERSTITIAL INFLAMMATION IN CHRONIC PROTEINURIC RENAL DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$294,121.00
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 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the suppo ....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 1500 Australians commence dialysis for this reason, and many more die of kidney failure or its complications. One of the major reasons for progression of kidney failure is that kidney cells produce a complex network of inflammatory mediators (cytokines) which attract inflammatory cells into the supporting tissue of the kidney (the interstitium). Recently, drugs that inhibit these cytokines have been used in animal models of chronic kidney disease. Such treatment regimens have been at most only partially effective because they have been directed against only one cytokine, and because they have ignored the fact that the profile of cytokines varies with stage of disease. This project will use a rodent model (Adriamycin nephrosis) of human chronic kidney disease to define strategies for preventing interstitial inflammation using anti-cytokine therapy. Our laboratory has identified three cytokines which appear to play a pivotal role in the development of interstitial inflammation in Adriamycin nephrosis, and shown that their production varies with time. Knowledge of the time-dependent interactions among and regulation of these cytokines will be used to define optimal delivery of therapy directed against all three cytokines. As anti-cytokine therapy is already being trialled in other types of (non-kidney) disease in humans, the success of such a therapeutic approach to treating progressive kidney disease in this animal model will have important and immediate implications for the treatment of chronic kidney disease in humans.Read moreRead less