Vitamin D3 Receptor Signalling To Prevent Kidney Failure Due To Polycystic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$468,009.00
Summary
Polycystic kidney disease (PKD) is the most common fatal inherited kidney disease in the world. Kidney failure is the most serious and life-threatening complication of PKD, but currently there is no treatment to prevent this problem. The aim of this project is to determine whether vitamin D3 can prevent kidney failure and hypertension due to PKD. The results of this project could lead to simple and cost-effective treatments to prevent kidney failure in patients suffering from PKD.
Two-photon Microscopy Of Albumin Handling By The Intact Kidney
Funder
National Health and Medical Research Council
Funding Amount
$346,602.00
Summary
The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per day. In the past, it has been considered that excessive pro ....The clinical association between protein loss in the urine and retention of salt, resulting in high blood pressure and progressive decline in kidney function, is well known. Under normal conditions, the kidneys filter 180 litres of water and reabsorb 1.7 kg of salt per day, a function which is principally performed by the kidney tubules in the kidney. Similarly the kidney tubule cells reabsorb and break down up to 3 grams of albumin per day. In the past, it has been considered that excessive protein loss in the urine is primarily due to problems in the filtering units of the kidneys, rather than due to abnormalities in the reabsorption of protein in the kidney tubules. However, we consider that common abnormalities in the processes within the kidney tubules that regulate both the reabsorption of salt and the excretion of acid may result in concomitant high blood pressure and increased protein loss in the kidney. Thus the overall aim of the project is to investigate the mechanisms by which the complex responsible for protein uptake determines the interrelationship between protein reabsorption and catabolism and the ion transporting proteins in the membrane of the proximal tubule. This project will use cutting-edge microscopic imaging technology to investigate the mechanisms of protein uptake in the intact kidney. This information will be integrated with data obtained from our molecular physiology experiments to define how the kidney handles protein. As persistent proteinuria is the most important predictor of tubulointerstitial pathology and progressive decline in renal function in almost all renal disease, the understanding of the precise mechanism by which this occurs is essential in the design of renoprotective therapies.Read moreRead less
TGFbeta Isoforms Differentially Regulate Fibrosis And Inflammation In Diabetic Nephropathy Via KLF Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$540,639.00
Summary
Progressive scarring and inflammation in the kidney represent the final common injury pathway for diseases that lead to kidney failure, including diabetic nephropathy. This project explores the interplay between the molecular processes that are triggered by high glucose levels in patients with diabetic nephropathy, some of which are deleterious and some potentially 'protective'. By understanding these mechanisms we will be able to prevent and more effectively treat kidney disease in diabetes.
Epithelial-mesenchymal Transformation In Diabetic Nephropathy: Roles Of Oxidative Stress And KLF Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$557,523.00
Summary
Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction ....Diabetes mellitus is responsible for the majority of kidney disease in the Western world . Diabetic nephropathy now accounts for the single largest cost to the health system in the USA. In Australia diabetic nephropathy, together with glomerulonephritis accounts for over 50% of the cases of dialysis-requiring renal failure. As the incidence of diabetes is increasing, current projections indicate an expotential rise in patient population with kidney disease. As the presence of kidney dysfunction is possibly the greatest predictor of subsequent cardiovascular events (including heart attack, heart failure and stroke) a thorough understanding of the mechanism of progressive kidney failure in patients with diabetes is required so that effective therapeutic strategies may be developed. Preliminary data leading to the development of this proposal, has shown that normal kidney tubule cells 'transform' into fibroblastic-like cells, in a process known as epithelial-mesenchymal transformation (EMT), under the metabolic disturbances inherent in diabetes mellitus. These fibroblast-like cells are likely to be responsible for the progressive scarring in the kidney that is characteristic of irreversible renal failure. We have documented that a specific factor, transforming growth factor beta (TGFB1) is increased in kidney cells in the presence of diabetes mellitus, and our preliminary data suggests the action of TGB1 is regulated by the KLF-family of transcription factors. This project aims to determine whether metabolic conditions such as exposure to high glucose and oxidative stress induced by diabetes mellitus modifies the KLF factors within cells that then alter susceptibility to TGFB1 induced EMT. The specific pathways involved in EMT will be dissected using both cell culture models and animal models of diabetes mellitus. These pathways will be selectively interrupted to assess reversibility of the EMT process.Read moreRead less
Circulating Low -molecular Weight AGEs In The Development And Progression Of Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$297,523.00
Summary
High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that progressively contributes to organ damage. AGEs also bind and activate specific rec ....High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that progressively contributes to organ damage. AGEs also bind and activate specific receptors that promote the damage and scarring of tissue. Where the glucose concentration is high, AGEs accumulate much more quickly. This is one reason why patients with good sugar control do better than those who are unable to control their blood sugars. The importance of this AGE pathway is illustrated by the fact that blocking the formation of AGEs is able to prevent kidney damage in animals with diabetes. In addition, exposure to AGEs can cause diabetes-like changes in the absence of high sugars. Our laboratory is a world leader in the study of the advanced glycation and methods blocking this process. The research proposed will investigate circulating levels of AGEs in experimental animals and patients with diabetes, and correlate them with the development and progression of complications of diabetesRead moreRead less
Resolvin E1 Is A Novel Anti-inflammatory And Anti-fibrotic Lipid Mediator For The Treatment Of Chronic Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$519,246.00
Summary
This project will ascertain whether a naturally occurring compound, Resolvin E1 with potent anti-inflammatory properties, can effectively halt the progression of experimental kidney disease. We will also test whether Resolvin E1 can exert other potential benefits in suppressing progressive fibrosis of the kidney. The outcome of this study will allow us to evaluate the therapeutical potential of Resolvin E1 for the treatment of acute and chronic kidney diseases.
Cardiovascular Disease; Priorities And Outcomes For People With Chronic And End Stage Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$81,976.00
Summary
This thesis will investigate the patterns, causes and effects of heart disease in chronic kidney disease patients; how heart disease impacts on hospital admission patterns and mortality over time. We will explore the relationship between cognition, cardiovascular and kidney disease; the impact on patient outcomes and quality of life. Finally, we will explore how current research funding reflects disease burden, research output and the stated priorities of patients with chronic kidney disease.
Acute injury can lead to chronic immune activation in both chronic kidney disease and in transplantation. We will study the role of a class of molecules, the purines, that are released by injury and lead to immune activation. We will focus on the molecular variations and pharmacological blockade of their receptors as potential treatments for kidney disease and transplant graft failure.