Contributions Of Intrinsic Renal Cells To Inflammatory Renal Injury
Funder
National Health and Medical Research Council
Funding Amount
$66,433.00
Summary
These studies aim to improve our understanding of glomeruonephritis, the most common cause of kidney failure. They will study the interactions between circulating white blood cells (leukocytes) which originate from the bone marrow , and intrinsic kidney cells in the development of tis disease. Inflammation is the result of recruitment of bone marrow derived inflammatory cells and plasma proteins to a variety of stimuli. The subsequent injury represents the interaction between recruited cells and ....These studies aim to improve our understanding of glomeruonephritis, the most common cause of kidney failure. They will study the interactions between circulating white blood cells (leukocytes) which originate from the bone marrow , and intrinsic kidney cells in the development of tis disease. Inflammation is the result of recruitment of bone marrow derived inflammatory cells and plasma proteins to a variety of stimuli. The subsequent injury represents the interaction between recruited cells and local cells within the target organ. Glomerulonephritis is an important human disease where both bone marrow derived inflammatory and local cells have the potential to contribute to kidney injury by production of signalling molecules called cytokines. This study will determine the contribution of specific cytokines produced by intrinsic renal cells towards the development of inflammatory kidney injury in GN.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
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
TAK1 - A Novel Regulator Of Renal Inflammation And Fibrosis.
Funder
National Health and Medical Research Council
Funding Amount
$537,704.00
Summary
Renal failure is a major health problem in our community. Recent in vitro studies have identified a protein that plays a critical role in the induction of inflammation and fibrosis - processes central to the progression of kidney disease. This project will use a genetic-based approach to determine if this regulator plays a critical role in the pathogenesis of experimental kidney disease. If successful, these studies will identify a new therapeutic target for the treatment of kidney disease.
Kidney disease occurs in up to 50% of patients with insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes. The increasing rate of diabetes in our community has made it a major cause of kidney disease and a growing health problem. Despite clinical attempts to control blood glucose and blood pressure levels, kidney disease in most diabetic patients progresses towards a complete loss of kidney function. In severe cases, the survival of the patient is dependent upon lifelong dialysi ....Kidney disease occurs in up to 50% of patients with insulin-dependent (type 1) and non-insulin-dependent (type 2) diabetes. The increasing rate of diabetes in our community has made it a major cause of kidney disease and a growing health problem. Despite clinical attempts to control blood glucose and blood pressure levels, kidney disease in most diabetic patients progresses towards a complete loss of kidney function. In severe cases, the survival of the patient is dependent upon lifelong dialysis or transplantation, which are costly and complicated treatments. Therefore, there is an urgent need to improve treatment stategies in diabetic patients to avoid kidney failure. Recent evidence in human and experimental models of diabetic kidney disease has indicated that macrophages infiltrate the kidney during the disease process. Our previous knowledge from other inflammatory kidney diseases suggests that macrophages play an important role in promoting the progression of disease and, in some of these diseases, treatment strategies which block macrophage function and accumulation have been shown to be effective in inhibiting the disease. The overall aim of these studies will be to determine the importance of macrophages in the pathogenesis of diabetic kidney disease and identify the mechanisms regulating their recruitment and activation within the diabetic kidney. This will be achieved by examining the progression of kidney disease in type 1 and type 2 diabetic mice which have been genetically modified to prevent macrophage accumulation and activation within the kidney. These studies will provide valuable information into the pathogenesis of diabetic kidney disease and will identify whether therapeutic strategies targeting macrophages can help prevent kidney loss in diabetes.Read moreRead less
Stress-activated Protein Kinases - A Common Pathway Of Progressive Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$581,750.00
Summary
Patients who progress to end-stage renal failure require treatment by life-long dialysis or kidney transplantation. In addition, renal failure is a strong and independent risk factor for heart attack. Renal failure is a major health problem in our community in terms of patient welfare and the substantial financial cost of renal replacement therapy and cardiac complications. Even with recent improvements in the control of blood pressure, we still have far to go in terms of halting progression and ....Patients who progress to end-stage renal failure require treatment by life-long dialysis or kidney transplantation. In addition, renal failure is a strong and independent risk factor for heart attack. Renal failure is a major health problem in our community in terms of patient welfare and the substantial financial cost of renal replacement therapy and cardiac complications. Even with recent improvements in the control of blood pressure, we still have far to go in terms of halting progression and disease remission. Current therapies are still based on non-specific anti-inflammatory drugs which have substantial, dose-limiting side effects. Indeed, our current therapies do not even target the some of the critical pathogenic processes of progressive kidney disease, such as apoptotic cell death and fibrosis. Therefore, it is important to identify common mechanisms of progressive kidney disease. Irrespective of the nature of the initial renal insult, progressive forms of kidney disease show common pathogenic processes of inflammation, apoptotic cell death and fibrosis that inexorably lead to end stage renal failure. Recent studies from our laboratory, and others, suggest that these three pathogenic processes operate via a common pathway called the SAPK (stress-activated protein kinases). This hypothesis will be tested by blocking the SAPK pathway in three different animal models of kidney disease which feature these key pathogenic processes (inflammation, apoptosis cell death and fibrosis). Blockade of the SAPK pathway will be achieved by means of pharmaceutical drugs and using gene deficient mice. If this hypothesis were proven, this would provide a well-defined therapeutic target for the treatment of progressive kidney disease. Indeed, since inhibitors of the SAPK pathway are already in clinical trials for other indications, targeting this mechanism in progressive kidney disease is a realistic goal.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