Molecular Mechanisms Linking Proteinuria And Sodium Retention
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
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 interrelationship between protein reabsorption and catabolism and Na+ reabsorption in the human kidney tubule. The project uses the combined methods of cultured human kidney tubules, biochemical and molecular biology techniques which are unavailable in other laboratories in Australia (and internationally). This project will comprehensively characterise the mechanisms of protein uptake and salt reabsorption in human kidney tubule cells when exposed to both normal and high concentrations of protein. The exact nature of the interaction of protein uptake with salt reabsorption and hence high blood pressure will be determined. As both hypertension and persistent proteinuria are the most important predictors of tubulointerstitial pathology and progressive decline in renal function in almost all renal disease, the understanding of the precise interaction between these two factors is essential in the design of renoprotective therapies.Read moreRead less
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
Pharmacological Preconditioning And Sodium/hydrogen Exchange Inhibition To Optimise Preservation Of The Donor Pig Heart
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Heart transplantation has become established as an extremely beneficial treatment for patients with end-stage heart failure, however its success is limited by the restricted availability of donor hearts. Many hearts that could be considered for heart transplantation cannot be used because of damage that can occur to potential donor hearts after the death of the donor. This damage is caused in part by deterioration in heart function after death and in part by the process of removal and cold stora ....Heart transplantation has become established as an extremely beneficial treatment for patients with end-stage heart failure, however its success is limited by the restricted availability of donor hearts. Many hearts that could be considered for heart transplantation cannot be used because of damage that can occur to potential donor hearts after the death of the donor. This damage is caused in part by deterioration in heart function after death and in part by the process of removal and cold storage that occur prior to transplantation of the heart. This study will examine two new methods of optimising the quality and preservation of the donor heart for transplantation. The treatments to be investigated in this study are aimed at preventing damage to the donor heart after death and during the process of transplantation. The studies will be conducted in a pig model of heart transplantation that we have developed in our laboratory. The treatments will be administered to the donor pig after induction of brain death and also to the recipient during transplantation of the heart. As the model closely mimics all aspects of human heart transplantation, any positive findings that stem from these studies will be directly applicable to human transplantation. Improved preservation of the donor heart will make the operation safer and will potentially increase the number of hearts that can be used for transplantation. As many donors provide multiple organs for transplantation eg kidneys, liver, lungs and pancreas, the treatments that we are investigating have the potential to improve the recovery of all these organs after transplantation.Read moreRead less
Altered Intracellular Signalling In Response To Hyperglycaemia Reflects An Inherent Predisposition To Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$164,061.00
Summary
Diabetic nephropathy affects 30-50% of patients with diabetes mellitus. The reasons as to why only a proportion of patients develop this devastating complication is not clear. Poor control of blood sugar levels has been well characterised as being of aetiological importance in its genesis, but is clearly not the sole factor responsible. Genetic factors appear to predispose individuals to developing diabetic nephropathy, with a significantly higher number of affected patients having a family hist ....Diabetic nephropathy affects 30-50% of patients with diabetes mellitus. The reasons as to why only a proportion of patients develop this devastating complication is not clear. Poor control of blood sugar levels has been well characterised as being of aetiological importance in its genesis, but is clearly not the sole factor responsible. Genetic factors appear to predispose individuals to developing diabetic nephropathy, with a significantly higher number of affected patients having a family history of hypertension and vascular disease. Our own preliminary studies using cells from human kidneys have demonstrated that there are clearly 2 responses observed with respect to alterations in intracellular signalling after exposure to high glucose concentrations and hormones known to be of importance in the development of diabetic nephropathy (such as angiotensin II and insulin-like growth factor-1). These responses appear to be specific to the patient from which the kidney tissue is derived. Thus the aim of the present study is to determine prospectively, whether the groups differ with regards their intracellular signalling and subsequent development of tubulointerstitial pathology in an in vitro model of diabetes mellitus.Read moreRead less
Our studies are aimed at examining how blood flow and pressure is controlled in the various tissues of the body. In particular, we hope to improve our understanding of how blood flow is matched to local metabolic requirements and how a constancy of conditions can be maintained despite changes in overall blood pressure. This ability to control local blood flow occurs through the ability of very small arteries to rapidly adjust their diameters through vasoconstriction or vasodilatation. The vessel ....Our studies are aimed at examining how blood flow and pressure is controlled in the various tissues of the body. In particular, we hope to improve our understanding of how blood flow is matched to local metabolic requirements and how a constancy of conditions can be maintained despite changes in overall blood pressure. This ability to control local blood flow occurs through the ability of very small arteries to rapidly adjust their diameters through vasoconstriction or vasodilatation. The vessels can thus act as valves regulating the transfer of blood flow and pressure to smaller vessels downstream. One particular response that small arteries exhibit is the ability to constrict when pressure within the vessels increases. The increase in pressure appears to stretch the vessel wall which in turn initiates a series of mechanical and biochemical steps that ultimately lead to contraction of muscle cells within the vessel wall. By contracting, the vessels limit the increase in downstream flow and pressure that would be expected to occur. The vessels being studied are very small, typically less than 100 micron. They are studied under isolated and controlled conditions using microscope and computer-based imaging techniques. While this allows us to directly monitor changes in vessel diameter to various stimuli (e.g. a change in pressure) we have also had to miniaturize biochemical measurements so we can understand the chemistry which underlies these vasoconstrictor responses. Understanding of how these local blood regulatory mechanisms occur is not only relevant to our understanding of the normal situation but is also vital to understanding disease states. For example, this work is very relevant to common cardiovascular disorders such as hypertension. It is hoped that a detailed understanding of the biochemical pathways by which small arteries contract will allow the design and targeting of pharmaceutical approaches for treatment of vascular disease states.Read moreRead less