Kidney failure is a devastating consequence of diabetes mellitus. Evidence exists that increased amounts of glucose are filtered by the kidney and then together with salt is reaborbed, in patients with diabetes. The increased glucose and salt reabsorption is considered to trigger cellular damage leading to renal failure. The studies will determine if reducing glucose and salt resportion by the kidney protects against the development of renal failure in models of diabetic renal disease.
A Central Role For Carbonic Anhydrase In Renal Hypertrophy And Interstitial Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$414,888.00
Summary
1 in 3 Australians are at risk of developing kidney disease. Renal replacement therapies (dialysis and transplantation) currently cost over $1.2 billion per year. These therapies do not address the underlying cause of the disease. Much research has focused on novel strategies to reverse kidney damage with mixed success. In this project we examine a novel preventative strategy based on currently available therapeutics that may slow the progression of kidney disease.
Understanding The Mechanistic Basis Of Microalbuminuria In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$613,757.00
Summary
The appearance of small amounts of albumin in the urine (microalbuminuria) in people with diabetes is a marker of progressive kidney disease, while microalbuminuria in the general population is a major risk factor for cardiovascular disease. The reason why microalbuminuria develops is poorly understood. This project will investigate dysfunction of kidney tubular cells as the mechanistic basis of microalbuminuria. If proven, this will provide a new link between kidney and cardiovascular disease.
Preventing Diabetic Complications Using Anti-inflammatory Peptides
Funder
National Health and Medical Research Council
Funding Amount
$805,146.00
Summary
The Receptor for Advanced Glycation End-products (RAGE) triggers inflammation. It was thought that this receptor was only activated from outside the cell. However, we discovered that other receptors can activate it from the inside. This is called trans-activation. During this ideas grant, we will develop innovative ways to block trans-activation of RAGE and translate these findings to make new therapeutics that are highly-relevant to he development and progression of diabetes.
We have validated CDA1 as an effective target to retard kidney disease in diabetes using a mouse model where we deleted the CDA1gene. We have also developed a novel agent to inhibit CDA1 in order to retard diabetic kidney disease. In this application, we propose to confirm the efficacy of targeting CDA1 using various diabetes models and a range of strategies to target CDA1. We will also rigorously explore translation of these findings to a new treatment for diabetic renal disease.
Role Of Growth And Transcription Factors In Tubulointerstitial Injury In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down collagen. This proposal will not only focus on how CTGF promotes ....Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down collagen. This proposal will not only focus on how CTGF promotes scarring but will explore 2 novel factors called Snail and Slug which can act directly on particular genes such as CTGF to inhibit these deleterious effects. By further characterising these pathways involving Snail, Slug and CTGF in the kidney it will be possible to generate new targets and therapies for various forms of progressive kidney disease including diabetic kidney disease.Read moreRead less
Does Excess Consumption Of Dietary Advanced Glycation End Products Activate The Complement Pathway Contributing To Diabetic Nephropathy?
Funder
National Health and Medical Research Council
Funding Amount
$470,617.00
Summary
Modern lifestyle is characterised by the consumption of foods that have been highly processed to improve their shelf life and flavour. However, this food processing has been shown to generate potentially harmful compounds, Advanced Glycation End Products (AGEs) that may promote inflammation and worsen diabetic kidney disease. This study investigates the effects of overeating a diet high in AGEs on the function of the kidney, and aims to find out how these AGEs lead to kidney damage.
Growth Factors And Their Effect On MicroRNAs And Transcription Factors In Tubulointerstitial Fibrosis In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$490,202.00
Summary
A common cause of kidney disease is diabetes and is partly related to increased expression and action of growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney by acting on a novel class of intracellular regulator molecules called microRNAs, to change the cell's characteristics such that cells begin laying down excess collagen. This proposal will focus on how growth factors act on microRNAs and the role of microRNAs in diabetic kidney disease.
The Role Of Toll-like Receptors In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$740,452.00
Summary
Diabetic nephropathy (DN) is the leading cause of chronic kidney disease globally and the No.1 cause of kidney failure requiring dialysis or transplantation in Australia. We are unsure why kidney scarring and failure develops in people with diabetes. Because of this, we have no specific treatments. Our studies suggest an immune receptor present in the kidney may be important. We aim to see whether absence of these receptors can prevent DN, thus identifying a specific target for treatment.
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