Aldosterone-induced endothelial glycocalyx dysfunction, a potential therapeutic target in proteinuria?

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In health the kidney act as a filter, keeping cells and proteins within our blood whilst allowing toxins to pass into the urine. The presence of a significant quantity of protein in the urine (proteinuria) indicates that the kidney filtering units, called glomeruli, have been damaged. Proteinuria is common affecting 4% of healthy adults and over 20 % of those with chronic kidney disease. It is important because the presence of proteinuria places individuals at a much higher risk of progressive kidney failure, heart attacks and strokes.In order for protein to leave the blood and enter the urine it has to pass through a number of cell layers collectively called the glomerular filtration barrier. This forms a key part of our kidneys and normally prevents protein from entering the urine. The barrier consists of two types of cell, podocytes and endothelial cells. The endothelial cells form the innermost layer of cells within our blood vessels. Endothelial cells are covered by an additional protective layer called the glycocalyx. This layer is produced by the endothelial cells and is a mix of proteins and sugars. It forms a jelly like covering on the cells surface. This layer has been found to have a number of important jobs. It regulates the passage of cells and proteins from the blood into the tissues. It detects how fast the blood is moving helping to regulate tissues blood flow and it prevents blood from clotting unnecessarilySo far a number of conditions have been shown to affect the glycocalyx, I believe that a hormone called Aldosterone is likely to damage the glycocalyx and that this damage results in protein leaking into the urine. Aldosterone is a hormone that helps animals regulate the amount of salt and water in their bodies. Its main action is on kidney cells to make them keep sodium within the body and loose potassium into the urine. When we are healthy the level of aldosterone in our blood is tightly regulated however the levels are increased in a number of conditions including; high blood pressure, obesity, renal failure, sleep disorders and by some medications (including ACE inhibitors and angiotensin receptor blockers which are commonly used in the UK to treat high blood pressure). Clinical studies in patients with proteinuria have shown that blocking aldosterone reduces the amount of protein that leaks from the blood into the urine preserving kidney function. Blocking aldosterone also helps patients with poor heart function. Kidney doctors are reluctant to prescribe aldosterone-blocking drugs, however, because of their side effects. In kidney disease potassium levels in the blood can become high. Blocking aldosterone can worsen this problem. If the potassium level becomes too high it can send the heart into a dangerous rhythm. This means most kidney patients miss out on an important drug that could help preserve their kidney function. My provisional work on human cells in the lab has shown that aldosterone damages the glycocalyx. The next step in my research is to confirm that aldosterone damages the glycocalyx in living animals. I think it is likely that aldosterone causes cells to make an enzyme called heparanase. When this is released into the blood this enzyme removes heparan sulphate from the glycocalyx damaging its structure. I believe if I can prevent this process I can protect the glycocalyx and potentially reduce proteinuria without causing high potassium levels.I will be working in the University of Bristol laboratories within a group focused on the glycocalyx within the kidney. The group has an excellent international reputation for work involving the glycocalyx and is led by renal physicians. In my role as a clinician I know that there is a clinical need for further therapies to reduce proteinuria. Studying this novel pathway may yield new therapeutic targets suitable for clinical practice free from the side effect of high potassium.